Heterocyclic compounds as ccr5 antagonists

ABSTRACT

The present invention relates to compounds of formula (I), or pharmaceutically acceptable derivatives thereof, useful in the treatment of CCR5-related diseases and disorders, for example, useful in the inhibition of HIV replication, the prevention or treatment of an HIV infection, and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).

BACKGROUND OF THE INVENTION

The human immunodeficiency virus (“HIV”) is the causative agent foracquired immunodeficiency syndrome (“AIDS”), a disease characterized bythe destruction of the immune system, particularly ofCD4^(+ T-cells, with attendant susceptibility to opportunistic infections, and its precursor AIDS-related complex (“ARC”), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.)

In addition to CD4, HIV requires a co-receptor for entry into targetcells. The chemokine receptors function together with CD4 asco-receptors for HIV. The chemokine receptors CXCR4 and CCR5 have beenidentified as the main co-receptors for HIV-1. CCR5 acts as a majorco-receptor for fusion and entry of macrophage-tropic HIV into hostcells. These chemokine receptors are thought to play an essential rolein the establishment and dissemination of an HIV infection. Therefore,CCR5 antagonists are thought to be useful as therapeutic agents activeagainst HIV.

We have now discovered a series of small molecule nonpeptide compoundsthat are useful as inhibitors of HIV replication.

BRIEF DESCRIPTION OF THE INVENTION

The present invention features compounds that are useful in theinhibition of HIV replication, the prevention of infection by HIV, thetreatment of infection by HIV and in the treatment of AIDS and/or ARC,either as pharmaceutically acceptable salts or pharmaceuticalcomposition ingredients. The present invention further features methodsof treating AIDS, methods of preventing infection by HIV, and methods oftreating infection by HIV as monotherapy or in combination with otherantivirals, anti-infectives, immunomodulators, antibiotics or vaccines.The present invention also features pharmaceutical compositions,comprising the above-mentioned compounds that are suitable for theprevention or treatment of CCR5-related diseases and conditions. Thepresent invention further features processes for making theabove-mentioned compounds.

SUMMARY OF THE INVENTION

The present invention includes compounds of formula (I)

and pharmaceutically acceptable derivatives thereof, wherein:

-   -   X is a C₁₋₅ alkylene chain, wherein said X is optionally        substituted by one or more ═O, ═S, —S(O)_(t)—, alkyl, or halogen        and wherein said C₁₋₅ alkylene chain may optionally have 0-3        heteroatoms selected from oxygen, phosphorus, sulfur, or        nitrogen;    -   Ring A is a saturated, partially saturated or aromatic 3-7        monocyclic or 8-10 membered bicyclic ring having one ring        nitrogen and 0-4 additional heteroatoms selected from oxygen,        phosphorus, sulfur, or nitrogen;    -   Ring B has an oxygen atom in addition to the depicted nitrogen;    -   R¹ is alkyl optionally substituted by one or more R⁷, alkenyl        optionally substituted by one or more R⁷, alkynyl optionally        substituted by one or more R⁷, cycloalkyl optionally substituted        by one or more R⁸, heterocyclyl optionally substituted by one or        more R⁸, heteroaryl optionally substituted by one or more R⁶, or        aryl optionally substituted by one or more R⁶; or R¹ and X taken        together form a saturated, partially saturated or aromatic 5-6        memebered ring having 0-3 heteroatoms selected from oxygen,        phosphorus, sulfur, or nitrogen that is fused to Ring A;    -   each R² is independently selected from —OR⁰, —C(O)-R⁰,        —S(O)₂-R⁰, —C(O)—N(R⁰)₂, —S(O)₂—N(R⁰)₂,        —(CH₂)_(a)-N(R⁰)(—V_(b)-R⁺), —(CH₂)_(a)-(—V_(b)-R⁺), halogen,        alkyl optionally substituted by one or more R⁷, alkenyl        optionally substituted by one or more R⁷, alkynyl optionally        substituted by one or more R⁷, aryl optionally substituted by        one or more R⁶, heteroaryl optionally substituted by one or more        R⁶, cycloalkyl optionally substituted by one or more R⁸, or        heterocyclyl optionally substituted by one or more R⁸; and two        adjacent R²s on Ring A are optionally taken together to form a        fused, saturated, partially saturated or aromatic 5-6 membered        ring having 0-3 heteroatoms selected from oxygen, phosphorus,        sulfur, or nitrogen; or two geminal R²s are optionally taken        together to form a spiro, saturated, partially saturated or        aromatic 5-4 membered ring having 0-3 heteroatoms selected from        oxygen, phosphorus, sulfur, or nitrogen, said fused or spiro        ring being optionally substituted by one or more R⁸;    -   each a independently is 0-3;    -   each b independently is 0 or 1;    -   V is —C(O)—, —C(O)O—, —S(O)₂—, or —C(O)—N(R⁰)—;    -   R⁺ is alkyl, cycloalkyl, aralkyl, aryl, heteroaryl,        heteroaralkyl, or heterocyclyl, wherein said R⁺ is optionally        substituted by one or more R⁸;    -   m is 0 or 1;    -   n is 0-5;    -   R³ is H, —N(R⁰)₂, —N(R⁰)C(O)R⁰, —CN, halogen, CF₃, alkyl        optionally substituted by one or more groups selected from R⁷ or        —S-aryl optionally substituted by —(CH₂)₁₋₆-N(R⁰)SO₂(R⁰),        alkenyl optionally substituted by one or more groups selected        from R⁷ or —S-aryl optionally substituted by        —(CH₂)₁₋₆-N(R⁰)SO₂(R⁰), alkynyl optionally substituted by one or        more groups selected from R⁷ or —S-aryl optionally substituted        by —(CH₂)₁₋₆-N(R⁰)SO₂(R⁰), cycloalkyl or carbocyclyl optionally        substituted by one or more R⁸, aryl optionally substituted by        one or more R⁶, heteroaryl optionally substituted by one or more        R⁶, or heterocyclyl optionally substituted by one or more R⁸;    -   Y is alkyl, alkenyl, alkynyl, —(CR⁴R⁵)_(p)—, —C(O)—, —C(O)C(O)—,        —C(S)—, —O—(CH₂)₀₋₄—C(O)—, —(CH₂)₀₋₄—C(O)—O—, —N(R⁰)—C(O)—,        —C(O)—N(R⁰)—, —N(R⁰)—C(S)—, —S(O)_(t)—, —O—C(═N—CN),        —O—C(═N—R⁰)—, —C(═N—CN)—O—, —C(═N—R⁰)—O—, —C(═N—CN)—S—,        —S—C(═N—CN)—, —N(R⁰)—C(═N—CN)—, —C(═N—CN)—,        —N(R⁰)—C[═N—C(O)—R⁰], —N(R⁰)—C[═N—S(O)_(t)—R⁰],        —N(R⁰)—C(═N—OR⁰)—, —N(R⁰)—C(═N—R⁰)—, or —C(═N—R⁰)—;    -   each R⁴ is independently H, alkyl optionally substituted by R⁷,        alkenyl optionally substituted by R⁷, or alkynyl optionally        substituted by R⁷;    -   each R⁵ is independently selected from H, —C(O)—OR⁶,        —C(O)—N(R⁰)₂, —S(O)₂—N(R⁰)₂, —S(O)₂—R⁰, aryl optionally        substituted by R⁶, or heteroaryl optionally substituted by R⁶;    -   p is 1-5;    -   each t independently is 1 or 2;    -   each R⁶ is independently selected from halogen, —CF₃, —OCF₃,        —OR⁰, —(CH₂)₁₋₆—OR⁰, —SR⁰, —(CH₂)₁₋₆—SR⁰, —SCF₃, —R⁰,        methylenedioxy, ethylenedioxy, —NO₂, —CN, —(CH₂)₁₋₆—CN, —N(R⁰)₂,        —(CH₂)₁₋₆—N(R⁰)₂, —NR⁰C(O)R⁰, —NR⁰(CN), —NR⁰C(O)N(R⁰)₂,        —NR⁰C(S)N(R⁰)₂, —NR⁰CO₂R⁰, —NR⁰NR⁰C(O)R⁰, —NR⁰NR⁰C(O)N(R⁰)₂,        —NR⁰NR⁰CO₂R⁰, —C(O)C(O)R⁰, —C(O)CH₂C(O)R⁰, —(CH₂)₀₋₆CO₂R⁰,        —O—C(O)R⁰, —C(O)R⁰, —C(O)N(R⁰)N(R⁰)₂, —C(O)N(R⁰)₂, —C(O)N(R⁰)OH,        —C(O)N(R⁰)SO₂R⁰, —OC(O)N(R⁰)₂, —S(O)_(t)R⁰, —S(O)_(t)—OR⁰,        —S(O)_(t)N(R⁰)C(O)R⁰, —S(O)_(t)N(R⁰)OR⁰, —NR⁰SO₂N(R⁰)₂,        —NR⁰SO₂R⁰, —C(═S)N(R⁰)₂, —C(═NH)—N(R⁰)₂, —(CH₂)₁₋₆—C(O)R⁰,        —C(═N—OR⁰)—N(R⁰)₂, —O—(CH₂)₀₋₆—SO₂N(R⁰)₂, —(CH₂)₁₋₆NHC(O)R⁰, or        —SO₂N(R⁰)₂ wherein the two R⁰s on the same nitrogen are        optionally taken together to form a 5-8 membered saturated,        partially saturated, or aromatic ring having additional 0-4        heteroatoms selected from oxygen, phosphorus, nitrogen, or        sulfur;    -   each R⁷ is independently selected from halogen, —CF₃, —R⁰, —OR⁰,        —OCF₃, —(CH₂)₁₋₆—OR⁰, —SR⁰, —SCF₃, —(CH₂)₁₋₆—SR⁰, aryl        optionally substituted by R⁶, methylenedioxy, ethylenedioxy,        —NO₂, —CN, —(CH₂)₁₋₆—CN, —N(R⁰)₂, —(CH₂)₁₋₆—N(R⁰)₂, —NR⁰C(O)R⁰,        —NR⁰(CN), —NR⁰C(O)N(R⁰)₂, —N(R⁰)C(S)N(R⁰)₂, —NR⁰CO₂R⁰, —NR⁰        NR⁰C(O)R⁰, —NR⁰NR⁰C(O)N(R⁰)₂, —NR⁰NR⁰CO₂R⁰, —C(O)C(O)R⁰,        —C(O)CH₂C(O)R⁰, —(CH₂)₀₋₆—CO₂R⁰, —C(O)R⁰, —C(O)N(R⁰)N(R⁰)₂,        —C(O)N(R⁰)₂, —C(O)N(R⁰)OH, —OC(O)R⁰, —C(O)N(R⁰)SO₂R⁰,        —OC(O)N(R⁰)₂, —S(O)_(t)R⁰, —S(O)_(t)—OR⁰, —S(O)_(t)N(R⁰)C(O)R⁰,        —S(O)_(t)N(R⁰)OR⁰, —NR⁰SO₂N(R⁰)₂, —NR⁰SO₂R⁰, —C(═S)N(R⁰)₂,        —C(═NH)—N(R⁰)₂, —(CH₂)₁₋₆—C(O)R⁰, —C(═N—OR⁰)—N(R⁰)₂,        —O—(CH₂)₀₋₆—SO₂N(R⁰)₂, —(CH₂)₁₋₆—NHC(O)R⁰, or —SO₂N(R⁰)₂ wherein        the two R⁰s on the same nitrogen are optionally taken together        to form a 5-8 membered saturated, partially saturated, or        aromatic ring having additional 0-4 heteroatoms selected from        oxygen, phosphorus, nitrogen, or sulfur;    -   each R⁸ is independently selected from R⁷, ═O, ═S, ═N(R⁰),        ═N(CN);    -   each R⁰ is independently selected from hydrogen, alkyl, alkenyl,        alkynyl, cycloalkyl, carbocyclylalkyl, aryl, heteroaryl,        aralkyl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl,        wherein each member of R⁰ except H is optionally substituted by        one or more R*, OR*, N(R*)₂, ═O, ═S, halo, CF₃, NO₂, CN,        —C(O)R*, —CO₂R*, —C(O)-aryl, —C(O)-heteroaryl, —C(O)-aralkyl,        —S(O)_(t)-aryl, —S(O)_(t)-heteroaryl, —NR*SO₂R*, —NR*C(O)R*,        —NR*C(O)N(R*)₂, —N(R*)C(S)N(R*)₂, —NR*CO₂R*, —NR*NR*C(O)R*,        —NR*NR*C(O)N(R*)₂, —NR*NR*CO₂R*, —C(O)C(O)R*, —C(O)CH₂C(O)R*,        —C(O)N(R*)N(R*)₂, —C(O)N(R*)₂, —C(O)NR*SO₂R*, —OC(O)N(R*)₂,        —S(O)_(t)R*, —NR*SO₂N(R*)₂, —SO₂N(R*)₂ wherein the two R*s on        the same nitrogen are optionally taken together to form a 5-8        membered saturated, partially saturated or aromatic ring having        additional 0-4 heteroatoms selected from oxygen, phosphorus,        nitrogen or sulfur; and    -   each R* is independently H, alkyl, alkenyl, alkynyl, cycloalkyl,        aryl, or heteroaryl.

In one embodiment R¹ is optionally substitued aryl, such as R¹ is phenylmono- or di-substituted with halogen, such as R¹ is phenyldi-substituted with Cl.

In one embodiment —(Y)_(m)—R³ suitably is

More suitably —(Y)_(m)—R³ is

In one embodiment m is 1, Y is —C(O)—, and R³ is aryl, heteroaryl,alkyl, or cycloalkyl, each optionally substituted.

In one embodiment m is 1, Y is —(C═N—CN)—O—, and R³ is optionallysubstituted aryl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heteroaryl, or optionally substitutedheterocyclyl.

In one embodiment m is 1, Y is —(CH₂)—, and R³ is optionally substitutedaryl.

In one embodiment m is 1, Y is —C(O)O—, and R³ is optionally substitutedalkyl or optionally substituted aryl.

In one embodiment m is 0 and R³ is optionally substituted heteroaryl oroptionally substituted heterocyclyl.

In one embodiment X is —(CH₂)—, —(CH₂—CH₂)—, or —CH₂—CH₂—CH₂)—. FurtherX is optionally substituted by one or more halogen or oxo. Still furtherX is disubstituted with halogen. Still further X is disubstituted withfluoro. Specifically X may be —(CF₂—CH₂)—. Further X optionally has 1-3heteroatoms selected from oxygen, phosphorus, sulfur, or nitrogen.

In one embodiment the A ring is selected from the following, where theasterisk (*) indicates the preferred, but not limiting, point(s) ofsubstitution:

Suitably each R², with the asterisk (*) indicating a preferred, but notlimiting, point of substitution from Ring A, independently is selectedfrom

In one embodiment the ring A, with two geminal R²s, is selected from:

Suitably the A ring is tropane or piperidine, either optionallysubstituted with one or more R². Preferrably, A—R² is comprised of oneof the following:

In one embodiment the A ring contains at least one additional nitrogenatom and said A ring optionally is N-substituted. Suitably the A ring isN-substituted with —(CH₂)_(a)—(V_(b)-R+).

One aspect of the invention includes the compounds of claim 1 whereinring B is as follows:

An additional aspect of the invention includes a method of treatmentincluding prevention of a viral infection in a mammal comprisingadministering to said mammal an antiviral effective amount of a compoundof the present invention. Preferably the viral infection is an HIVinfection.

An additional aspect of the invention includes a method of treatmentincluding prevention of a bacterial infection in a mammal comprisingadministering to said mammal an effective amount of a compound of thepresent invention. Preferably the bacterium is Yersinia pestis.

An additional aspect of the invention includes a method of treatmentincluding prevention of multiple sclerosis, rheumatoid arthritis,autoimmune diabetes, chronic implant rejection, asthma, rheumatoidarthritis, Crohns Disease, inflammatory bowel disease, chronicinflammatory disease, glomerular disease, nephrotoxic serum nephritis,kidney disease, Alzheimer's Disease, autoimmune encephalomyelitis,arterial thrombosis, allergic rhinitis, arteriosclerosis, Sjogren'ssyndrome (dermatomyositis), systemic lupus erythematosus, graftrejection, cancers with leukocyte infiltration of the skin or organs,infectious disorders including bubonic and pneumonic plague, humanpapilloma virus infection, prostate cancer, wound healing, amyotrophiclateral sclerosis and immune mediated disorders in a mammal comprisingadministering to said mammal a pharmceutically effective amount of acompound of the present invention.

An additional aspect of the invention includes a compound of the presentinvention for use in medical therapy.

An additional aspect of the invention includes the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment including prophylaxis of a viral infection. Preferably theviral infection is a HIV infection.

An additional aspect of the invention includes the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment including prophylaxis of a bacterial infection. Preferably thebacterium is Yersinia pestis.

An additional aspect of the invention includes the use of a compound ofthe present invention in the manufacture of a medicament for thetreatment including prophylaxis of multiple sclerosis, rheumatoidarthritis, autoimmune diabetes, chronic implant rejection, asthma,rheumatoid arthritis, Crohns Disease, inflammatory bowel disease,chronic inflammatory disease, glomerular disease, nephrotoxic serumnephritis, kidney disease, Alzheimer's Disease, autoimmuneencephalomyelitis, arterial thrombosis, allergic rhinitis,arteriosclerosis, Sjogren's syndrome (dermatomyositis), systemic lupuserythematosus, graft rejection, cancers with leukocyte infiltration ofthe skin or organs, infectious disorders including bubonic and pneumonicplague, human papilloma virus infection, prostate cancer, wound healing,amyotrophic lateral sclerosis and immune mediated disorders.

An additional aspect of the invention includes a pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundof the present invention together with a pharmaceutically acceptablecarrier. Preferably the pharmaceutical composition is in the form of atablet, capsule, or liquid.

An additional aspect of the invention includes a method of treatmentincluding prevention of a viral infection in a mammal comprisingadministering to said mammal a composition comprising a compound of thepresent invention and another therapeutic agent. Preferably thecomposition further includes another therapeutic agent selected from thegroup consisting of (1-alpha, 2-beta,3-alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine [(−)BHCG, SQ-34514,lobucavir], 9-[(2R,3R,4S)-3,4-bis(hydroxymethyl)-2-oxetanosyl]adenine(oxetanocin-G), acyclic nucleosides, acyclovir, valaciclovir,famciclovir, ganciclovir, penciclovir, acyclic nucleoside phosphonates,(S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC),[[[2-(6-amino-9H-purin-9-yl)ethoxy]methyl]phosphinylidene]bis(oxymethylene)-2,2-dimethylpropanoicacid (bis-POM PMEA, adefovir dipivoxil),[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid(tenofovir),(R)-[[2-(6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acidbis-(isopropoxycarbonyloxymethyl)ester (bis-POC-PMPA), ribonucleotidereductase inhibitors, 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl)thiocarbonohydrazone and hydroxyurea, nucleoside reverse transcriptaseinhibitors, 3′-azido-3′-deoxythymidine (AZT, zidovudine),2′,3′-dideoxycytidine (ddC, zalcitabine), 2′,3′-dideoxyadenosine,2′,3′-dideoxyinosine (ddI, didanosine), 2′,3′-didehydrothymidine (d4T,stavudine), (−)-beta-D-2,6-diaminopurine dioxolane (DAPD),3′-azido-2′,3′-dideoxythymidine-5′-H-phosphophonate (phosphonovir),2′-deoxy-5-iodo-uridine (idoxuridine),(−)-cis-1-(2-hydroxymethyl)-1,3-oxathiolane 5-yl)-cytosine (lamivudine),cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC),3′-deoxy-3′-fluorothymidine, 5-chloro-2′,3′-dideoxy-3′-fluorouridine,(−)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol(abacavir), 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G),ABT-606 (2HM-H2G) ribavirin, protease inhibitors, indinavir, ritonavir,nelfinavir, amprenavir, saquinavir, fosamprenavir,(R)-N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-N-[(R-2-N-(isoquinolin-5-yloxyacetyl)amino-3-methylthlopropanoyl]amino-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide(KNI-272),4R-(4alpha,5alpha,6beta)]-1,3-bis[(3-aminophenyl)methyl]hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-onedimethanesulfonate (mozenavir),3-[1-[3-[2-(5-trifluoromethylpyridinyl)-sulfonylamino]phenyl]propyl]-4-hydroxy-6alpha-phenethyl-6beta-propyl-5,6-dihydro-2-pyranone(tipranavir),N′-[2(S)-Hydroxy-3(S)-[N-(methoxycarbonyl)-1-tert-leucylamino]-4-phenylbutyl-Nalpha-(methoxycarbonyl)-N′-[4-(2-pyridyl)benzyl]-L-tert-leucylhydrazide(BMS-232632),3-(2(S)-Hydroxy-3(S)-(3-hydroxy-2-methylbenzamido)-4-phenylbutanoyl)-5,5-dimethyl-N-(2-methylbenzyl)thiazolidine-4(R)-carboxamide(AG-1776),N-(2(R)-hydroxy-1(S)-indanyl)-2(R)phenyl-methyl-4(S)-hydroxy-5-(1-(1-(4-benzo[b]furanylmethyl)-2(S)-N′-(tert-butylcarboxamido)piperazinyl)pentanamide(MK-944A), interferons, α-interferon, renal excretion inhibitors,probenecid, nucleoside transport inhibitors, dipyridamole,pentoxifylline, N-acetylcysteine (NAC), Procysteine, α-trichosanthin,phosphonoformic acid, immunomodulators, interleukin II, thymosin,granulocyte macrophage colony stimulating factors, erythropoetin,soluble CD₄ and genetically engineered derivatives thereof,non-nucleoside reverse transcriptase inhibitors (NNRTIs), nevirapine(BI-RG-587),alpha-((2-acetyl-5-methylphenyl)amino)2,6-dichloro-benzeneacetamide(loviride),1-[3-(isopropylamino)-2-pyridyl]-4-[5-(methanesulfonamido)-1H-indol-2-ylcarbonyl]piperazinemonomethanesulfonate (delavirdine), (10R, 11S, 12S)-12-hydroxy-6, 6, 10,11-tetramethyl-4-propyl-11,12-dihydro-2H, 6H,10H-benzo(1,2-b:3,4-b′:5,6-b″)tripyran-2-one ((+) calanolide A),(4S)-6-Chloro-4-[1E)-cyclopropylethenyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (DPC-083),(S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one(efavirenz, DMP 266),1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-2,4(1H,3H)-pyrimidinedione(MKC-442), and5-(3,5-dichlorophenyl)thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethylcarbamate (capravirine), glycoprotein 120 antagonists, PRO-2000,PRO-542,1,4-bis[3-[(2,4-dichlorophenyl)carbonylamino]-2-oxo-5,8-disodiumsulfanyl]naphthalyl-2,5-dimethoxyphenyl-1,4-dihydrazone (FP-21399), cytokine antagonists,reticulose (Product-R), 1,1′-azobis-formamide (ADA),1,11-(1,4-phenylenebis(methylene))bis-1,4,8,11-tetraazacyclotetradecaneoctahydrochloride (AMD-3100), integrase inhibitors, and fusioninhibitors.

An additional aspect of the invention includes a method of treatmentincluding prevention of a viral infection in a mammal comprisingadministering to said mammal a composition comprising a compound of thepresent invention and ritonavir.

DETAILED DESCRIPTION OF THE INVENTION

The phrase “optionally substituted” is used interchangeably with thephrase “substituted or unsubstituted” or with the term“(un)substituted.” Unless otherwise indicated, an optionally substitutedgroup may have a substituent at each substitutable position of thegroup, and each substitution is independent of the other.

The term “alkyl”, alone or in combination with any other term, refers toa straight-chain or branched-chain saturated aliphatic hydrocarbonradical containing the specified number of carbon atoms. Examples ofalkyl radicals include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,n-hexyl and the like.

The term “cycloalkyl”, “carbocylyl”, “carbocyclic”, or “carbocycle”, or“carbocyclo”, alone or in combination with any other term, refers to amonocyclic or polycyclic non-aromatic hydrocarbon ring radical havingthree to twenty carbon atoms, preferably from three to twelve carbonatoms, and more preferably from three to ten carbon atoms. Ifpolycyclic, each ring in a carbocylyl radical is non-aromatic unlessotherwise indicated. A carbocylyl radical is either completely saturatedor contains one or more units of unsaturation but is not aromatic. Theunsaturation, if present, may occur in any point in the ring that mayresult in any chemically stable configuration. The term “cycloalkyl”,“carbocylyl”, “carbocyclic”, or “carbocycle”, or “carbocyclo” alsoincludes hydrocarbon rings that are fused to one or more aromatic rings,such as in tetrahydronaphthyl, where the radical or point of attachmentis on the non-aromatic ring.

Unless otherwise indicated, the term “cycloalkyl”, “carbocylyl”,“carbocyclic”, or “carbocycle”, or “carbocyclo” also includes eachpossible positional isomer of a non-aromatic hydrocarbon radical, suchas in 1-decahydronaphthyl, 2-decahydronaphthyl, 1-tetrahydronaphthyl and2-tetrahydronaphthyl. Examples of suitable cycloalkyl groups include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, decahydronaphthyl, tetrahydronaphthyl and thelike.

The term “alkenyl,” alone or in combination with any other term, refersto a straight-chain or branched-chain alkyl group with at least onecarbon-carbon double bond. Examples of alkenyl radicals include, but arenot limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl,pentenyl, hexenyl, hexadienyl and the like.

The term “alkynyl” refers to hydrocarbon groups of either a straight orbranched configuration with one or more carbon-carbon triple bonds whichmay occur in any stable point along the chain, such as ethynyl,propynyl, butynyl, pentynyl, and the like.

The term “alkoxy” refers to an alkyl ether radical, wherein the term“alkyl” is defined above. Examples of suitable alkyl ether radicalsinclude, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

The term “aryl”, alone or in combination with any other term, refers toan aromatic monocyclic or polycyclic hydrocarbon ring radical containingfive to twenty carbon atoms, preferably from six to fourteen carbonatoms, and more preferably from six to ten carbon atoms. Also includedwithin the scope of the term “aryl”, as it is used herein, is a group inwhich an aromatic hydrocarbon ring is fused to one or more non-aromaticcarbocyclic or heteroatom-containing rings, such as in an indanyl,phenanthridinyl or tetrahydronaphthyl, where the radical or point ofattachment is on the aromatic hydrocarbon ring.

Unless otherwise indicated, the term “aryl” also includes each possiblepositional isomer of an aromatic hydrocarbon radical, such as in1-naphthyl, 2-naphthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl,1-phenanthridinyl, 2-phenanthridinyl, 3-phenanthridinyl,4-phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl,9-phenanthridinyl and 10-phenanthridinyl. Examples of aryl radicalsinclude, but are not limited to, phenyl, naphthyl, indenyl, azulenyl,fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl,phenanthridinyl and the like.

The term “aralkyl” further refers to groups of -R_(a)R_(b), where R_(a)is an alkylene as defined herein and R_(b) is an aryl as defined herein.

The term “heterocycle”, “heterocyclic”, and “heterocyclyl”, alone or incombination with any other term, refers to a non-aromatic monocyclic orpolycyclic ring radical containing three to twenty carbon atoms,preferably three to seven carbon atoms if monocyclic and eight to elevencarbon atoms if bicyclic, and in which one or more ring carbons,preferably one to four, are each replaced by a heteroatom such as N, O,and S. If polycyclic, each ring in a heterocyclyl radical isnon-aromatic unless otherwise indicated. A heterocyclic ring may befully saturated or may contain one or more units of unsaturation but isnot aromatic. The unsaturation, if present, may occur in any point inthe ring that may result in any chemically stable configuration. Theheterocyclic ring may be attached at a carbon or heteroatom that resultsin the creation of a stable structure. Preferred heterocycles include5-7 membered monocyclic heterocycles and 8-10 membered bicyclicheterocycles.

Also included within the scope of the term “heterocycle”,“heterocyclic”, or “heterocyclyl” is a group in which a non-aromaticheteroatom-containing ring is fused to one or more aromatic rings, suchas in an indolinyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl,where the radical or point of attachment is on the non-aromaticheteroatom-containing ring. Unless otherwise indicated, the term“heterocycle”, “heterocyclic”, or “heterocyclyl” also includes eachpossible positional isomer of a heterocyclic radical, such as in1-decahydroquinoline, 2-decahydroquinoline, 3-decahydroquinoline,4-decahydroquinoline, 5-decahydroquinoline, 6-decahydroquinoline,7-decahydroquinoline, 7-decahydroquinoline, 8-decahydroquinoline,4a-decahydroquinoline, 8a-decahydroquinoline, 1-indolinyl, 2-indolinyl,3-indolinyl, 1-tetrahydroquinoline, 2-tetrahydroquinoline,3-tetrahydroquinoline and 4-tetrahydroquinoline. The term“heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl.

Examples of heterocyclic groups include, but are not limited to,imidazolinyl, 2,3-dihydro-1H-imidazolyl, imidazolidinyl, indazolinolyl,perhydropyridazyl, pyrrolinyl, pyrrolidinyl, 4H-pyrazolyl, piperidinyl,pyranyl, pyrazolinyl, piperazinyl, morpholinyl, thiamorpholinyl,thiazolidinyl, thiamorpholinyl, oxopiperidinyl, oxopyrrolidinyl,azepinyl, tetrahydrofuranyl, oxoazepinyl, tetrahydropyranyl, thiazolyl,dioxolyl, dioxinyl, oxathiolyl, benzodioxolyl, dithiolyl, dithiolanyl,tetrahydrothiophenyl, sulfolanyl, dioxanyl, dioxolanyl,tetahydrofurodihydrofuranyl, dihydropyranyl,tetrahydropyranodihydrofuranyl, tetradyrofurofuranyl,tetrahydropyranofuranyl, diazolonyl, phthalimidinyl, benzoxanyl,benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl andbenzothianyl.

The term “heteroaryl”, alone or in combination with any other term,refers to an aromatic monocyclic or polycyclic ring radical containingfive to twenty carbon atoms, preferably five to ten carbon atoms, inwhich one or more ring carbons, preferably one to four, are eachreplaced by a heteroatom such as N, O, and S. Preferred heteroarylgroups include 5-6 membered monocyclic heteroaryls and 8-10 memberedbicyclic heteroaryls.

Also included within the scope of the term “heteroaryl” is a group inwhich a heteroaromatic ring is fused to one or more aromatic ornon-aromatic rings where the radical or point of attachment is on theheteroaromatic ring. Examples include, but are not limited to,pyrido[3,4-d]pyrimidinyl, 7,8-dihydro-pyrido[3,4-d]pyrimidine and5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine. Unless otherwise indicated,the term “heteroaryl” also includes each possible positional isomer of aheteroaryl radical, such as in 2-pyrido[3,4-d]pyrimidinyl and4-pyrido[3,4-d]pyrimidinyl.

Examples of heteroaryl groups include, but are not limited to,imidazolyl, quinolyl, isoquinolyl, indolyl, indazolyl, pyridazyl,pyridyl, pyrrolyl, pyrazolyl, pyrazinyl, quinoxalyl, pyrimidinyl,pyridazinyl, furyl, thienyl, triazolyl, thiazolyl, carbazolyl,carbolinyl, tetrazolyl, benzofuranyl, oxazolyl, benzoxazolyl,isoxozolyl, isothiazolyl, thiadiazolyl, furazanyl, oxadiazolyl,benzimidazolyl, benzothienyl, quinolinyl, benzotriazolyl,benzothiazolyl, isoquinolinyl, isoindolyl, acridinyl andbenzoisoxazolyl.

The term “heteroaralkyl” further refers to groups of -R_(a)R_(b), whereR_(a) is an alkylene as defined herein and R_(b) is a heteroaryl asdefined herein.

The term “heteroatom” means nitrogen, oxygen, phosphorus, or sulfur andincludes any oxidized forms thereof, including as non-limiting examplesoxidized forms of nitrogen such as N(O) {N⁺—O⁻}, oxidized forms ofsulfur such as S(O) and S(O)₂, and the quaternized form of any basicnitrogen.

The term “halogen” refers to fluorine, chlorine, bromine or iodine.

The term “pharmaceutically effective amount” refers to an amount of acompound of the invention that is effective in treating a CCR5-relateddisease, for example a virus infection, for example an HIV infection, ina patient either as monotherapy or in combination with other agents. Theterm “treatment” as used herein refers to the alleviation of symptoms ofa particular disorder in a patient, or the improvement of anascertainable measurement associated with a particular disorder, and mayinclude the suppression of symptom recurrence in an asymptomatic patientsuch as a patient in whom a viral infection has become latent. The term“prophylaxis” refers to preventing a disease or condition or preventingthe occurrence of symptoms of such a disease or condition, in a patient.As used herein, the term “patient” refers to a mammal, including ahuman.

The term “pharmaceutically acceptable carrier” refers to a carrier thatmay be administered to a patient, together with a compound of thisinvention, and which does not destroy the pharmacological activitythereof and is nontoxic when administered in doses sufficient to delivera therapeutic amount of the therapeutic agent.

The term “pharmaceutically acceptable derivative” means anypharmaceutically acceptable salt, ester, salt of an ester, or otherderivative of a compound of this invention which, upon administration toa recipient, is capable of providing (directly or indirectly) a compoundof this invention or an inhibitorily active metabolite or residuethereof. Particularly favored derivatives and prodrugs are those thatincrease the bioavailability of the compounds of this invention whensuch compounds are administered to a mammal (e.g., by allowing an orallyadministered compound to be more readily absorbed into the blood) orwhich enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

Pharmaceutically acceptable salts of the compounds according to theinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acidsinclude hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic andbenzenesulfonic acids. Other acids, such as oxalic, while not inthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Salts derived from appropriate bases include alkali metal (e.g. sodium),alkaline earth metal (e.g., magnesium), ammonium, NW₄ ⁺ (wherein W isC₁₋₄ alkyl) and other amine salts. Physiologically acceptable salts of ahydrogen atom or an amino group include salts of organic carboxylicacids such as acetic, lactic, tartaric, malic, isethionic, lactobionicand succinic acids; organic sulfonic acids such as methanesulfonic,ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids andinorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamicacids. Physiologically acceptable salts of a compound with a hydroxygroup include the anion of said compound in combination with a suitablecation such as Na⁺, NH₄ ⁺, and NW₄ ⁺ (wherein W is a C₁₋₄alkyl group).

Any reference to any of the above compounds also includes a reference toa pharmaceutically acceptable salt thereof.

Salts of the compounds of the present invention may be made by methodsknown to a person skilled in the art. For example, treatment of acompound of the present invention with an appropriate base or acid in anappropriate solvent will yield the corresponding salt.

Esters of the compounds of the present invention are independentlyselected from the following groups: (1) carboxylic acid esters obtainedby esterification of the hydroxy groups, in which the non-carbonylmoiety of the carboxylic acid portion of the ester grouping is selectedfrom straight or branched chain alkyl (for example, acetyl, n-propyl,t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl(for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl(for example, phenyl optionally substituted by, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

In such esters, unless otherwise specified, any alkyl moiety presentadvantageously contains from 1 to 18 carbon atoms, particularly from 1to 6 carbon atoms, more particularly from 1 to 4 carbon atoms, Anycycloalkyl moiety present in such esters advantageously contains from 3to 6 carbon atoms. Any aryl moiety present in such esters advantageouslycomprises a phenyl group.

The compounds according to the invention contain one or more asymmetriccarbon atoms and thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereoisomers.All such isomeric forms of these compounds are expressly included in thepresent invention. Each stereogenic carbon may be of the R or Sconfiguration. Although the specific compounds exemplified in thisapplication may be depicted in a particular stereochemicalconfiguration, compounds having either the opposite stereochemistry atany given chiral center or mixtures thereof are also envisioned.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare also within the scope of this invention.

Certain compounds of this invention may exist in alternative tautomericforms. All such tautomeric forms of the present compounds are within thescope of the invention. Unless otherwise indicated, the representationof either tautomer is meant to include the other.

The present invention features compounds according to the invention foruse in medical therapy, for example for the treatment includingprophylaxis of viral infections such as an HIV infections and associatedconditions. Reference herein to treatment extends to prophylaxis as wellas the treatment of established infections, symptoms, and associatedclinical conditions such as AIDS related complex (ARC), Kaposi'ssarcoma, and AIDS dementia.

The present invention features use of the compounds of the presentinvention in the manufacture of a medicament for the treatment includingprophylaxis of a CCR5-related disease or condition, for example, a viralinfection, for example, an HIV infection.

According to another aspect, the present invention provides a method forthe treatment including prevention of the symptoms or effects of a viralinfection in an infected animal, for example, a mammal including ahuman, which comprises treating said animal with a pharmaceuticallyeffective amount of a compound according to the invention. According toone aspect of the invention, the viral infection is a retroviralinfection, in particular an HIV infection. A further aspect of theinvention includes a method for the treatment or prevention of thesymptoms or effects of an HBV infection.

The compounds according to the invention may also be used in adjuvanttherapy in the treatment of HIV infections or HIV-associated symptoms oreffects, for example Kaposi's sarcoma.

The compounds of the present invention may also be used in the treatmentincluding prevention of other CCR5-related diseases and conditions,including multiple sclerosis, rheumatoid arthritis, autoimmune diabetes,chronic implant rejection, asthma, rheumatoid arthritis, Crohns Disease,inflammatory bowel disease, chronic inflammatory disease, glomerulardisease, nephrotoxic serum nephritis, kidney disease, Alzheimer'sDisease, autoimmune encephalomyelitis, arterial thrombosis, allergicrhinitis, arteriosclerosis, Sjogren's syndrome (dermatomyositis),systemic lupus erythematosus, graft rejection, cancers with leukocyteinfiltration of the skin or organs, human papilloma virus infection,prostate cancer, wound healing, amyotrophic lateral sclerosis, immunemediated disorders.

The present invention further provides a method for the treatment of aclinical condition in an animal, for example, a mammal including a humanwhich clinical condition includes those which have been discussedhereinbefore, which comprises treating said animal with apharmaceutically effective amount of a compound according to theinvention. The present invention also includes a method for thetreatment including prophylaxis of any of the aforementioned diseases orconditions.

In yet a further aspect, the present invention provides the use of acompound according to the invention in the manufacture of a medicamentfor the treatment including prophylaxis of any of the above mentionedviral infections or conditions.

The above compounds according to the invention and theirpharmaceutically acceptable derivatives may be employed in combinationwith other therapeutic agents for the treatment of the above infectionsor conditions. Combination therapies according to the present inventioncomprise the administration of a compound of the present invention or apharmaceutically acceptable derivative thereof and anotherpharmaceutically active agent. The active ingredient(s) andpharmaceutically active agents may be administered simultaneously ineither the same or different pharmaceutical compositions or sequentiallyin any order. The amounts of the active ingredient(s) andpharmaceutically active agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect.

Examples of such therapeutic agents include agents that are effectivefor the treatment of viral infections or associated conditions. Amongthese agents are (1-alpha, 2-beta,3-alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine [(−)BHCG, SQ-34514,lobucavir], 9-[(2R,3R,4S)-3,4-bis(hydroxymethyl)-2-oxetanosyl]adenine(oxetanocin-G), acyclic nucleosides, for example acyclovir,valaciclovir, famciclovir, ganciclovir, and penciclovir, acyclicnucleoside phosphonates, for example(S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC),[[[2-(6-amino-9H-purin-9-yl)ethoxy]methyl]phosphinylidene]bis(oxymethylene)-2,2-dimethylpropanoicacid (bis-POM PMEA, adefovir dipivoxil),[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid(tenofovir), and(R)-[[2-(6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acidbis-(isopropoxycarbonyloxymethyl)ester (bis-POC-PMPA), ribonucleotidereductase inhibitors, for example 2-acetylpyridine5-[(2-chloroanilino)thiocarbonyl) thiocarbonohydrazone and hydroxyurea,nucleoside reverse transcriptase inhibitors, for example3′-azido-3′-deoxythymidine (AZT, zidovudine), 2′,3′-dideoxycytidine(ddC, zalcitabine), 2′,3′-dideoxyadenosine, 2′,3′-dideoxyinosine (ddI,didanosine), 2′,3′-didehydrothymidine (d4T, stavudine),(−)-beta-D-2,6-diaminopurine dioxolane (DAPD),3′-azido-2′,3′-dideoxythymidine-5′-H-phosphophonate (phosphonovir),2′-deoxy-5-iodo-uridine (idoxuridine),(−)-cis-1-(2-hydroxymethyl)-1,3-oxathiolane 5-yl)-cytosine (lamivudine),cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC),3′deoxy-3′-fluorothymidine, 5-chloro-2′,3′-dideoxy-3′-fluorouridine,(−)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol(abacavir), 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]guanine (H2G),ABT-606 (2HM-H2G) and ribavirin, protease inhibitors, for exampleindinavir, ritonavir, nelfinavir, amprenavir, saquinavir, fosamprenavir,(R)-N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-N-[(R)-2-N-(isoquinolin-5-yloxyacetyl)amino-3-methylthlopropanoyl]amino-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide(KNI-272),4R-(4alpha,5alpha,6beta)]-1,3-bis[(3-aminophenyl)methyl]hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-onedimethanesulfonate (mozenavir),3-[1-[3-[2-(5-trifluoromethylpyridinyl)-sulfonylamino]phenyl]propyl]-4-hydroxy-6alpha-phenethyl-6beta-propyl-5,6-dihydro-2-pyranone(tipranavir),N′-[2(S)Hydroxy-3(S)-[N-(methoxycarbonyl)-1-tert-leucylamino]-4-phenylbutyl-N^(alpha)-(methoxycarbonyl)-N′-[4-(2-pyridyl)benzyl]-L-tert-leucylhydrazide(BMS-232632),3-(2(S)-Hydroxy-3(S)-(3-hydroxy-2-methylbenzamido)-4-phenylbutanoyl)-5,5-dimethyl-N-(2-methylbenzyl)thiazolidine-4(R)-carboxamide(AG-1776), N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenyl-methyl-4(S)-hydroxy-5-(1-(1-(4benzo[b]furanylmethyl)-2(S)-N′-(tert-butylcarboxamido)piperazinyl)pentanamide(MK-944A), interferons such as α-interferon, renal excretion inhibitorssuch as probenecid, nucleoside transport inhibitors such asdipyridamole; pentoxifylline, N-acetylcysteine (NAC), Procysteine,α-trichosanthin, phosphonoformic acid, as well as immunomodulators suchas interleukin II or thymosin, granulocyte macrophage colony stimulatingfactors, erythropoetin, soluble CD₄ and genetically engineeredderivatives thereof, non-nucleoside reverse transcriptase inhibitors(NNRTIs), for example nevirapine (BI-RG-587),alpha-((2-acetyl-5-methylphenyl)amino)-2,6-dichloro-benzeneacetamide(loviride),1-[3-(isopropylamino)-2-pyridyl]4-[5-(methanesulfonamido)-1H-indol-2-ylcarbonyl]piperazinemonomethanesulfonate (delavirdine), (10R, 11S, 12S)-12-Hydroxy-6, 6, 10,11-tetramethyl-4-propyl-11,12-dihydro-2H, 6H, 10H-benzo(1,2-b:3,4-b′:5,6-b″)tripyran-2-one ((+) calanolide A),(4S)-6-Chloro-4-[1E)-cyclopropylethenyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)quinazolinone(DPC-083),(S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one(efavirenz, DMP 266),1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-2,4(1H,3H)-pyrimidinedione (MKC-442), and5-(3,5-dichlorophenyl)thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethylcarbamate (capravirine), glycoprotein 120 antagonists, for examplePRO-2000, PRO-542 and1,4bis[3-[(2,4-dichlorophenyl)carbonylamino]-2-oxo-5,8-disodiumsulfanyl]naphthalyl-2,5-dimethoxyphenyl-1,4-dihydrazone(FP-21399), cytokine antagonists, for example reticulose (Product-R),1,1′-azobis-formamide (ADA),1,11-(1,4-phenylenebis(methylene))bis-1,4,8,11-tetraazacyclotetradecaneoctahydrochloride (AMD-3100), integrase inhibitors, or fusioninhibitors, for example T-20 and T-1249.

The present invention further includes the use of a compound accordingto the invention in the manufacture of a medicament for simultaneous orsequential administration with at least another therapeutic agent, suchas those defined hereinbefore.

Compounds of the present invention may be administered with an agentknown to inhibit or reduce the metabolism of compounds, for exampleritonavir. Accordingly, the present invention features a method for thetreatment including prophylaxis of a disease as hereinbefore describedby administration of a compound of the present invention in combinationwith a metabolic inhibitor. Such combination may be administeredsimultaneously or sequentially.

In general a suitable dose for each of the above-mentioned conditionswill be in the range of 0.01 to 250 mg per kilogram body weight of therecipient (e.g. a human) per day, suitably in the range of 0.1 to 100 mgper kilogram body weight per day and most suitably in the range 0.5 to30 mg per kilogram body weight per day and particularly in the range 1.0to 20 mg per kilogram body weight per day. Unless otherwise indicated,all weights of active ingredient are calculated as the parent compoundof formula (I); for salts or esters thereof, the weights would beincreased proportionally. The desired dose may be presented as one, two,three, four, five, six or more sub-doses administered at appropriateintervals throughout the day. In some cases the desired dose may begiven on alternative days. These sub-doses may be administered in unitdosage forms, for example, containing 10 to 1000 mg or 50 to 500 mg,suitably 20 to 500 mg, and most suitably 50 to 400 mg of activeingredient per unit dosage form.

While it is possible for the active ingredient to be administered aloneit is preferable to present it as a pharmaceutical composition. Thecompositions of the present invention comprise at least one activeingredient, as defined above, together with one or more acceptablecarriers thereof and optionally other therapeutic agents. Each carriermust be acceptable in the sense of being compatible with the otheringredients of the composition and not injurious to the patient.

Pharmaceutical compositions include those suitable for oral, rectal,nasal, topical (including transdermal, buccal and sublingual), vaginalor parenteral (including subcutaneous, intramuscular, intravenous,intradermal, and intravitreal) administration. The compositions mayconveniently be presented in unit dosage form and may be prepared by anymethods well known in the art of pharmacy. Such methods represent afurther feature of the present invention and include the step ofbringing into association the active ingredients with the carrier, whichconstitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers or finelydivided solid carriers or both, and then if necessary shaping theproduct.

The present invention further includes a pharmaceutical composition ashereinbefore defined wherein a compound of the present invention or apharmaceutically acceptable derivative thereof and another therapeuticagent are presented separately from one another as a kit of parts.

Compositions suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Such patchessuitably contain the active compound 1) in an optionally buffered,aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3)dispersed in a polymer. A suitable concentration of the active compoundis about 1% to 25%, suitably about 3% to 15%. As one particularpossibility, the active compound may be delivered from the patch byelectrotransport or iontophoresis as generally described inPharmaceutical Research 3 (6), 318 (1986).

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,caplets, cachets or tablets each containing a predetermined amount ofthe active ingredients; as a powder or granules; as a solution or asuspension in an aqueous or non-aqueous liquid; or as an oil-in-waterliquid emulsion or a water-in-oil liquid emulsion. The active ingredientmay also be presented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredients in afree-flowing form such as a powder or granules, optionally mixed with abinder (e.g. povidone, gelatin, hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (e.g. sodium starchglycollate, cross-linked povidone, cross-linked sodium carboxymethylcellulose) surface-active or dispersing agent. Molded tablets may bemade by molding a mixture of the powdered compound moistened with aninert liquid diluent in a suitable machine. The tablets may optionallybe coated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredients therein using, for example,hydroxypropylmethyl cellulose in varying proportions to provide thedesired release profile. Tablets may optionally be provided with anenteric coating, to provide release in parts of the gut other than thestomach.

Pharmaceutical compositions suitable for topical administration in themouth include lozenges comprising the active ingredients in a flavoredbase, usually sucrose and acacia or tragacanth; pastilles comprising theactive ingredient in an inert basis such as gelatin and glycerin, orsucrose and acacia; and mouthwashes comprising the active ingredient ina suitable liquid carrier.

Pharmaceutical compositions suitable for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayPharmaceutical compositions containing in addition to the activeingredient such carriers as are known in the art to be appropriate.

Pharmaceutical compositions for rectal administration may be presentedas a suppository with a suitable carrier comprising, for example, cocoabutter or a salicylate or other materials commonly used in the art. Thesuppositories may be conveniently formed by admixture of the activecombination with the softened or melted carrier(s) followed by chillingand shaping in molds.

Pharmaceutical compositions suitable for parenteral administrationinclude aqueous and nonaqueous isotonic sterile injection solutionswhich may contain anti-oxidants, buffers, bacteriostats and soluteswhich render the pharmaceutical composition isotonic with the blood ofthe intended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents; and liposomesor other microparticulate systems which are designed to target thecompound to blood components or one or more organs. The pharmaceuticalcompositions may be presented in unit-dose or multi-dose sealedcontainers, for example, ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described.

Unit dosage pharmaceutical compositions include those containing a dailydose or daily subdose of the active ingredients, as hereinbeforerecited, or an appropriate fraction thereof.

It should be understood that in addition to the ingredients particularlymentioned above the pharmaceutical compositions of this invention mayinclude other agents conventional in the art having regard to the typeof pharmaceutical composition in question, for example, those suitablefor oral administration may include such further agents as sweeteners,thickeners and flavoring agents.

EXAMPLES

The following examples are intended for illustration only and are notintended to limit the scope of the invention in any way.

Low resolution, open-access LC-MS data were acquired in either ESIpos/neg or APCI pos/neg mode with scanning from 100-1100 amu @ 0.5sec/scan.

LC conditions: flowrate 0.8 mL/min. 85% H2O (0.1% formic acid) to 100%MeOH (0.075% formic acid) in 6 minutes. Phenomenex Max-RP column, 2.0×50mm.

High Resolution Mass Spectra were acquired using Micromass LCT massspectrometer (time-of-flight) with flow injection (FIA-MS) at 0.3 mL/minwith 100% MeOH (0.1% formic acid), run time of 2 minutes, in ESI+ mode,scanning from 100-1100 amu @ 0.5 sec/scan. Reserpine was used as thelock mass (m/z 609.2812) and to adjust mass scale.

As will be appreciated by those skilled in the art, the followingschemes may be followed in preparing the compounds of the presentinvention. Any variability depicted within the scheme(s) illustratedherein should be limited to the particular scheme and not necessarilyextended throughout the rest of the present specification.

Preparation of 5-chloro-3-phenylpent-1-en-3-ol

Anhydrous CeCl₃ (16 g, 64.9 mmol) was stirred vigorously in 100 mL THFfor 2h 15 min. The suspension was then cooled to −78° C. and a 1 Msolution of vinylmagnesiumbromide (62 mL, 62.3 mmol) was added. After1.5h at −78° C., a solution of 3-chloropropiophenone (7 g, 14.5 mmol) in20 mL THF was added dropwise via cannula. The reaction mixture wasstirred for 1 h, then gradually warmed to room temperature and quenchedby the addition of saturated aqueous NaHCO₃. Extraction into EtOAc (3×)followed by purification by silica gel chromatography (4:1hexanes:EtOAc) afforded the 5-chloro-3-phenylpent-1-en-3-ol (7.7 g, 94%)as a yellow oil; ¹H NMR (400 MHz, CDCl₃): δ 7.45-7.34 (m, 4H), 7.28 (m,1H), 6.18 (dd, 1H, J=17.2, 10.6 Hz), 5.34 (d, 1H, J=17.2 Hz), 5.23 (d,1H, J=10.8 Hz), 3.59 (td, 1H, J=10.6, 5.5 Hz), 3.41 (td, 1H, J=10.5, 5.5Hz), 2.40 (m, 2H), 2.0 (br. s, 1H).

Preparation of 5-chloro-3-phenylpentane-1,3-diol

To a 0° C. solution of 5-chloro-3-phenylpent-1-en-3-ol (6.12 g, 31.12mmol) in 125 mL THF was added a 1M solution of BH₃.THF (62.2 mL, 62.2mmol) dropwise. The reaction mixture was stirred for 3h at 0° C., and 5MNaOH (38 mL, 190 mmol) was slowly added, followed by 30% H₂O₂ (56 mL,495 mmol). After stirring for 90 min at room temperature, the organiclayer was isolated and the aqueous layer extracted with EtOAc. Theorganic layers were pooled, washed with saturated aqueous Na₂S₂O₃ andsaturated aqueous NH₄Cl, dried (Na₂SO₄), filtered, and passed through asilica plug to provide 5-chloro-3-phenylpentane-1,3-diol (4.3 g, 64%) asan oil. ¹H NMR (400 MHz, CDCl₃): δ 7.43-7.34 (m, 5H), 7.27 (m, 1H), 3.80(td, 1H, J=10.8, 4.2 Hz), 3.67-3.52 (m, 2H), 3.22 (td, 1H, J=10.5, 5.1Hz), 2.38 (ddd, 1H, J=13.7, 10.3, 5.9 Hz), 2.28 (ddd, 1H, J=13.7, 10.4,5.1 Hz), 2.23 (m, 1H), 2.03 (ddd, 1H, J=14.8, 4.6, 2.9 Hz).

Preparation of1-{[tert-butyl(dimethyl)silyl]oxy}-5-chloro-3-phenylpentan-3-ol

To a 0° C. solution of 5-chloro-3-phenylpentane-1,3-diol (4.3 g, 20mmol) and Et₃N (3.4 mL, 24 mmol) in 20 mL DMF, was addedtert-butyldimethylsilyl chloride (3.3 g, 21 mmol). After stirring for 2hat 0° C., the reaction mixture was diluted with EtOAc, washed withsaturated aqueous NaHCO₃, dried (Na₂SO₄) and chromatographed (9:1hex:EtOAc) to provide1-{[tert-butyl(dimethyl)silyl]oxy}-5-chloro-3-phenylpentan-3-ol (5.2 g,79%) as a clear oil. ¹H NMR (400 MHz, CDCl₃): δ 7.40-7.32 (m, 4H), 7.25(m, 1H), 4.88 (s, 1H), 3.73 (dt, 1H, J=10.3, 4.0 Hz), 3.65 (ddd, 1H,J=11.5, 10.6,5.1 Hz), 3.44 (td, 1H, J=10.6, 2.7 Hz), 3.15 (ddd, 1H,J=11.3, 10.6, 5.1 Hz), 2.34 (ddd, 1H, J=13.3, 11.4, 5.1 Hz), 2.27-2.15(m, 2H), 1.96 (dt, 1H, J=14.6, 3.2 Hz), 0.86 (s, 9H), −0.02 (s, 3H),−0.09 (s, 3H); ESI-MS 351 (M+Na).

Preparation of1-azido-5-{[tert-butyl(dimethyl)silyl]oxy}-3-phenylpentan-3-ol

A solution of1-{[tert-butyl(dimethyl)silyl]oxy}-5-chloro-3-phenylpentan-3-ol ((5.2 g,15.7 mmol) and NaN₃ (7.8 g, 120 mmol) in 50 mL DMF was stirred for 24hat 65° C. The reaction mixture was then diluted with EtOAc, washed withwater, dried, filtered and evaporated in vacuo to provide1-azido-5-{[tert-butyl(dimethyl)silyl]oxy) 3-phenylpentan-3-ol inquantitative yield as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.40-7.32(m, 4H), 7.24 (m, 1H), 4.89 (s, 1H), 3.72 (dt, 1H, J=10.3, 3.9 Hz),3.47-3.36 (m, 2H), 2.97 (ddd, 1H, J=12.3, 10.1, 5.5 Hz), 2.24-2.10 (m,2H), 2.07-1.93 (m, 2H), 0.86 (s, 9H), −0.02, (s, 3H), −0.09 (s, 3H);ESI-MS 358 (M+Na).

Preparation of6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinane

A solution of1-azido-5-{[tert-butyl(dimethyl)silyl]oxy}-3-phenylpentan-3-ol (1.19,3.3 mmol) in 30 mL EtOAc was stirred for 2h under 40 psi of H₂ gas inthe presence of catalytic 10% Pd/C. After filtration through celite, thereaction mixture was evaporated to give1-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-3-phenylpentan-3-ol inquantitative yield as a clear oil that was used without furtherpurification. ESI-MS 310 (M+H), 332 (M+Na).

A solution of the above amino alcohol (288 mg, 0.93 mmol) andp-formaldehyde (300 mg, 10 mmol) in 9 mL MeOH was heated under refluxfor 90 min. The reaction mixture was then filtered, concentrated invacuo, and the residue was redissolved in 3 mL CH₂Cl₂, Et₃N (0.40 mL,2.9 mmol) and trimethylacetyl chloride (0.23 mL, 1.9 mmol) were added,and the reaction was stirred for 24 h. After washing with saturatedaqueous NaHCO₃, the organic phase was isolated, dried (Na₂SO₄),concentrated and chromatographed (3:1 hex:EtOAc) to provide6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinane(290 mg, 71%) as a clear oil. ¹H NMR (400 MHz, CDCl₃): δ 7.41-7.34 (m,4H), 7.28 (m, 1H), 5.41 (d, 1H, J=10.6 Hz), 4.66 (d, 1H, J=10.8 Hz),4.21 (m, 1H), 3.55 (dt, 1H, J=10.4, 7.2 Hz), 3.33 (dt, 1H, J=10.4, 7.3Hz), 3.06 (br. t, 1H, J=11.8 Hz), 2.35 (ddd, 1H, J=14.2, 4.3, 3.0 Hz),2.07 (ddd, 1H, J=14.3, 11.3, 4.2 Hz), 1.97 (m, 2H), 1.28 (s, 9H), 0.83(s, 9H), −0.05 (s, 3H), −0.06 (s, 3H); ¹³C NMR (100 MHz, CHCl₃) 176.9,142.0, 128.7, 127.3, 126.4, 78.6, 72.0, 58.6, 46.4, 40.3, 38.8, 33.5,28.5, 25.9, 18.2, −5.4; ESI-MS 406 (M+H), 428 (M+Na).

Preparation of[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde

6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinane(4.07 g, 10.03 mmol) was stirred in a 1 M solution of tetrabutylammoniumfluoride in THF (40 mL, 40 mmol) for 2h at room temperature. Saturatedaqueous NaHCO₃ was added, and the reaction mixture was extracted withCHCl₃. The organic layers were dried (Na₂SO₄), concentrated and theresidue was filtered through a silica plug flushing with 1:1 hex:EtOActo afford2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethanol inquantitative yield as a clear oil that was used without furtherpurification. ¹H NMR (400 MHz, CDCl₃): δ 37.45-7.37 (m, 4H), 7.31 (m,1H), 5.51 (dd, 1H, J=10.9, 2.1 Hz), 4.69 (d, 1H, J=11.0 Hz), 4.30 (m,1H), 3.58 (m, 2H), 2.99 (m, 1H), 2.31 (dt, 1H, J=14.1, 3.4 Hz), 2.16(ddd, 1H, J=14.1, 11.7, 4.4 Hz), 2.04 (ddd, 1H, J=14.5, 7.0, 4.7 Hz),1.92 (ddd, 1H, J=14.6, 6.9, 4.7 Hz), 1.28 (s, 9H).

To a 0° C. solution of the above2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethanol,dimethyl sulfoxide (10 mL, 141 mmol) and diisopropylethylamine (10.5 mL,60 mmol) in 60 mL CH₂Cl₂ was added SO₃.pyr (9.0 g, 57 mmol) in oneportion. The reaction mixture was stirred at 0° C. for 2h, quenched withsaturated aqueous NaHCO₃, extracted with CHCl₃, dried (Na₂SO₄) andchromatographed (2:1 Hex:EtOAc) to provide[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (2.84g, 98%) as an oil. ¹H NMR (400 MHz, CDCl₃): δ 9.64 (t, 1H, J=2.7 Hz),7.45-7.41 (m, 4H), 7.33 (m, 1H), 5.49 (dd, 1H, J=11.1, 1.9 Hz), 4.74 (d,1H, J=11.5 Hz), 4.27 (m, 1H), 3.08 (m, 1H), 2.72 (AB_(q)d, 2H, J=15.3,2.8 Hz), 2.43 (ddd, 1H, J=14.2, 4.1, 3.0 Hz), 2.11 (ddd, 1H, J=14.2;11.4, 4.3 Hz), 1.28 (s, 9H). ESI-MS 312 (M+Na).

Example 1 Preparation of1-((1R,5S)-8-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole

To a solution of[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (50.4mg, 0.17 mmol),1-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazoledihydrochloride (64 mg, 0.17 mmol) and diisopropylethylamine (0.063 mL,0.35 mmol) in 2 mL CH₂Cl₂ was added sodium triacetoxyborohydride (55 mg,0.26 mmol) and the reaction mixture was stirred for 2h at roomtemperature. After evaporation, the residue was chromatographed (5% (2MNH₃/MeOH) in CHCl₃) to provide1-((1R,5S)-8-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole(50.4 mg, 56%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.65 (m,1H), 7.43-7.34 (m, 4H), 7.32-7.26 (m, 2H), 7.19-7.11 (m, 2H), 5.43 (s,1H, J=11.2 Hz), 4.70 (d, 1H, J=10.3 Hz), 4.61 (m, 1H), 4.21 (m, 1H),3.42-3.22 (m, 2H), 3.08 (m, 1H), 2.57 (s, 3H), 2.43-1.57 (m, 14H), 1.28(s, 9H); ESI-MS 515 (M+H), 237 (M+Na).

Example 2 Preparation of3-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-1-[4-(methylsulfonyl)phenyl]hex-5-en-2-one

3-(1-2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-1-[4-(methylsulfonyl)phenyl]hex-5-en-2-one(26 mg, 49%) was obtained as a white solid from[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (25mg, 0.087 mmol),1-[4-(methylsulfonyl)phenyl]-3-piperidin-4-ylhex-5-en-2-one (44 mg, 0.13mmol), diisopropylethylamine (0.033 mL, 0.19 mmol) and sodiumtriacetoxyborohydride (27 mg, 0.13 mmol) following the procedure inexample 1. ¹H NMR (400 MHz, CDCl₃), δ 7.90-7.86 (m, 2H), 7.44-7.36 (m,4H), 7.35-7.29 (m, 3H), 5.86 (m, 1H), 5.44 (d, 1H, J=10.4 Hz), 5.31-5.18(m, 2H), 4.83-4.59 (m, 2H), 4.15-3.83 (m, 3H), 3.73 (s, 2H), 3.29-1.66(m, 15H), 3.04 (s, 3H), 1.26 (s, 9H); ESI-MS 610 (M+H), 632 (M+Na).

Example 3 Preparation of6-(2-{4-[5-(4-chlorophenyl)-1H-pyrazol-3-yl]piperidin-1-yl}ethyl)-3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinane

6-(2-{4-[5-(4-chlorophenyl)-1H-pyrazol-3-yl]piperidin-1-yl}ethyl)-3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinane(35.0 mg, 75%) was obtained as a white solid from[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (25mg, 0.087 mmol), 4-[5-(4-chlorophenyl)-1H-pyrazol-3-yl]piperidine (34mg, 0.13 mmol), diisopropylethylamine (0.033 mL, 0.19 mmol) and sodiumtriacetoxyborohydride (27 mg, 0.13 mmol) following the procedure inexample 1. ¹H NMR (400 MHz, CDCl₃), δ 7.77-7.50 (m, 2H), 7.45-7.28 (m,7H), 6.33 (s, 1H), 5.44 (d, 1H, J=11.0 Hz), 4.79 (m, 1H), 4.12 (m, 1H),3.37-2.98 (m, 3H), 2.77 (m, 1H), 2.51-1.42 (m, 13H), 1.28 (s, 9H);ESI-MS 535 (M+H), 557 (M+Na).

Example 4 Preparation of2-benzyl-8-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}-2,8-diazaspiro[4,5]decan-1-one

2-benzyl-8-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}-2,8-diazaspiro[4.5]decan-1-one(25 mg, 56%) was obtained as a white solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (25mg, 0.087 mmol), 2-benzyl-2,8-diazaspiro[4.5]decan-1-one (37 mg, 0.13mmol), diisopropylethylamine (0.033 mL, 0.19 mmol) and sodiumtriacetoxyborohydride (27 mg, 0.13 mmol) following the procedure inexample 1. ¹H NMR (400 MHz, CDCl₃), δ 7.42-7.27 (m, 8H), 7.19-7.15 (m,2H), 5.42 (d, 1H, J=11.2 Hz), 4.76 (m, 1H), 4.40 (s, 2H), 4.13 (m, 1H),3.52 (m, 1H), 3.25-3.00 (m, 3H), 2.74 (m, 1H), 2.37-1.51 (m, 13H), 1.28(s, 9H); ESI-MS 518 (M+H).

Example 5 Preparation of1-((1R,5S)-8-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole

1-((1R,5S)-8-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole(22.8 mg, 44%) was obtained as a solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (30mg, 0.10 mmol),1-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazole (24.1mg, 0.1 mmol), and polymer supported-triacetoxyborohydride (200 mg, 0.6mmol) following the procedure in example 1. ¹H NMR (300 MHz, CDCl₃), δ7.70 (m, 1H), 7.59-7.44 (m, 5H), 7.37 (m, 1H), 7.28-7.18 (m, 2H), 5.49(d, 1H, J=10.8 Hz), 4.82 (d, 1H, J=10.8 Hz), 4.53 (m, 1H), 4.27 (m, 1H),3.51-3.33 (m, 2H), 3.20 (m, 1H), 2.61 (s, 3H), 2.70-2.29 (m, 5H),2.26-1.94 (m, 5H), 1.80-1.54 (m, 4H), 1.34 (s, 9H); ESI-MS 515 (M+H).

Example 6 Preparation of3-(2,2-dimethylpropanoyl)-6-{2-[4-(2-naphthyl)piperidin-1-yl]ethyl}-6-phenyl-1,3-oxazinane

3-(2,2-dimethylpropanoyl)-6-{2-[4-(2-naphthyl)piperidin-1-yl]ethyl}-6-phenyl-1,3-oxazinane(28.0 mg, 58%) was obtained as a solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (30mg, 0.10 mmol), 4-(2-naphthyl)piperidine (24.8 mg, 0.1 mmol), andpolymer supported-triacetoxyborohydride (200 mg, 0.6 mmol) following theprocedure in example 1. ¹H NMR (300 MHz, CDCl₃), δ 7.93-7.76 (m, 3H),7.70-7.32 (m, 9H), 5.47 (d, 1H, J=10.9 Hz), 4.81 (m, 1H), 4.24 (br.,1H), 3.27-2.80 (m, 5H), 2.75-1.84 (m, 11H), 1.34 (s, 9H); ESI-MS 485(M+H).

Example 7 Preparation of6-chloro-N-[(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)methyl]-1,3-benzothiazol-2-amine

6-chloro-N-[(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)methyl]-1,3-benzothiazol-2-amine(25.4 mg, 46%) was obtained as a solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (30mg, 0.10 mmol),6-chloro-N-(piperidin-4-ylmethyl)-1,3-benzothiazol-2-amine (17.5 mg, 0.1mmol), and polymer supported-triacetoxyborohydride (200 mg, 0.6 mmol)following the procedure in example 1. ¹H NMR (300 MHz, CDCl₃), δ7.66-7.55 (m, 1H), 7.50-7.26 (m, 7H), 5.65 (br., 1H), 5.45 (d, 1H,J=10.9 Hz), 4.77 (d, 1H, J=10.8 Hz), 4.21 (m, 1H), 3.47-3.29 (m, 2H),3.25-2.91 (m, 3H), 2.55-1.30 (m, 13H), 1.32 (s, 9H); ESI-MS 555 (M+H).

Example 8 Preparation of1-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-1H-indole

1-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-1H-indole(28.1 mg, 59%) was obtained as a solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (30mg, 0.10 mmol), 1-piperidin-4-yl-1H-indole (23.7 mg, 0.1 mmol), andpolymer supported-triacetoxyborohydride (200 mg, 0.6 mmol) following theprocedure in example 1. ¹H NMR (300 MHz, CDCl₃), δ 7.61 (d, 1H, J=7.7Hz), 7.45-7.35 (m, 4H), 7.36-7.29 (m, 2H), 7.08 (t, 1, J=7.2 Hz), 6.50(d,₁H, J=3.2 Hz), 5.43 (d, 1H, J=10.8 Hz), 4.72 (d, 1H, J=10.8 Hz),4.29-4.14 (m, 2H), 3.16-2.95 (m, 3H), 2.45-1.90 (m, 12H), 1.29 (s, 9H);ESI-MS 474 (M+H), 486 (M+Na).

Example 9 Preparation of 4-nitrobenzylallyl(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)carbamate

4-nitrobenzylallyl(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)carbamate(34.1 mg, 57%) was obtained as a solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (30mg, 0.10 mmol), 4-nitrobenzyl allyl(piperidin-4-yl)carbamate (31.9 mg,0.1 mmol), and polymer supported-triacetoxyborohydride (200 mg, 0.6mmol) following the procedure in example 1. ¹H NMR (400 MHz, CDCl₃), δ8.19 (m, 2H), 7.46 (m, 2H), 7.40-7.31 (m, 4H), 7.28 (m, 1H), 5.76 (m,1H), 5.39 (d, 1H, J=11.0 Hz), 5.23-5.03 (m, 4H), 4.67 (d, 1H, J=10.8Hz), 4.20 (m, 1H), 3.98 (br., 1H), 3.87-3.74 (m, 3H), 3.10-2.77 (m, 3H),2.36-1.57 (m, 11H), 1.26 (s, 9H); ESI-MS 593 (M+H), 615 (M+Na).

Example 10 Preparation ofN-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-N-ethyl-2-(4-nitrophenyl)acetamide

N-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-N-ethyl-2-(4-nitrophenyl)acetamide(36.6 mg, 65%) was obtained as a solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (30mg, 0.10 mmol), N-ethyl-2-(4-nitrophenyl)-N-piperidin-4-ylacetamide(29.1 mg, 0.1 mmol), and polymer supported-triacetoxyborohydride (200mg, 0.6 mmol) following the procedure in example 1. ¹H NMR (400 MHz,CDCl₃), δ 8.15 (m, 2H), 7.43-7.26 (m, 7H), 5.39 (d, 1H, J=10.9 Hz), 4.66(m, 1H), 4.36 (m, 1H), 4.19 (m, 1H), 3.76 (m, 2H), 3.27 (m, 3H),3.09-2.74 (m, 4H), 2.36-1.53 (m, 10H), 1.26 (s, 9H), 1.09 (m, 3H);ESI-MS 565 (M+H), 587 (M+Na).

Example 11 Preparation of5-chloro-1-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one

5-chloro-1-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one(32.9 mg, 62%) was obtained as a solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (30mg, 0.10 mmol),5-chloro-1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (25.2 mg,0.1 mmol), and polymer supported-triacetoxyborohydride (200 mg, 0.6mmol) following the procedure in example 1. ¹H NMR (300 MHz, CDCl₃), δ9.70 (s, 1H), 7.44-7.27 (m, 5H), 7.22-7.05 (m, 2H), 7.01 (m, 1H), 5.44(d, 1H, J=10.8 Hz), 4.71 (d, 1H, J=11.1 Hz), 4.35-4.16 (m, 2H),3.16-2.93 (m, 3H), 2.50-1.88 (m, 11H), 1.83-1.67 (m, 2H), 1.29 (s, 9H);ESI-MS 525 (M+H).

Example 12 Preparation ofN-allyl-N-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-2-phenylacetamide

N-allyl-N-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-2-phenylacetamide(34.0 g, 64%) was obtained as a solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (30mg, 0.10 mmol), N-allyl-2-phenyl-N-piperidin-4-ylacetamide (25.8 mg, 0.1mmol), and polymer supported-triacetoxyborohydride (200 mg, 0.6 mmol)following the procedure in example 1. ¹H NMR (400 MHz, CDCl₃), δ7.40-7.16 (m, 10H), 5.78 (m, 1H), 5.39 (d, 1H, J=11.1 Hz), 5.24-5.13 (m,2H), 5.04 (m, 1H), 4.67 (m, 1H), 4.49 (m, 1H), 4.19 (m, 1H), 3.94-3.46(m, 5H), 3.14-2.65 (m, 3H), 2.36-1.49 (m, 10H), 1.26 (s, 9H); ESI-MS 532(M+H).

Example 13 Preparation ofN-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-N-ethyl-2-(4-fluorophenyl)acetamide

N-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-N-ethyl-2-(4-fluorophenyl)acetamide(34.0 mg, 63%) was obtained as a solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (30mg, 0.10 mmol), N-ethyl-2-(4-fluorophenyl)-N-piperidin-4-ylacetamide(26.4 mg, 0.1 mmol), and polymer supported-triacetoxyborohydride (200mg, 0.6 mmol) following the procedure in example 1. ¹H NMR (400 MHz,CDCl₃), δ 7.41-7.26 (m, 5H), 7.21-7.14 (m, 2H), 7.00-6.94 (m, 2H), 5.39(d, 1H, J=10.8 Hz), 4.67 (m, 1H), 4.37 (m, 1H), 4.19 (m, 1H), 3.69-3.59(m, 2H), 3.51-2.67 (m, 8H), 2.36-1.54 (m, 9H), 1.26 (s, 9H), 1.15 (m,3H); ESI-MS 538 (M+H), 560 (M+Na).

Example 14 Preparation of4-{2-[(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)(ethyl)amino]-2-oxoethyl}benzamide

4-{2-[(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)(ethyl)amino]-2-oxoethyl}benzamide(14.5 mg, 26%) was obtained as a solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (30mg, 0.10 mmol), 4-{2-[ethyl(piperidin-4-yl)amino]-2-oxoethyl}benzamide(28.9 mg, 0.1 mmol), and polymer supported-triacetoxyborohydride (200mg, 0.6 mmol) following the procedure in example 1. ¹H NMR (300 MHz,CDCl₃), δ 7.75 (d, 2H, J=8.1 Hz), 7.41-7.35 (m, 2H0, 7.35-7.28 (m, 5H),6.11 (br., 1H), 5.61 (br., 1H), 5.41 (m, 1H), 4.70 (m, 1H), 4.47 (br.,1H), 4.18 (m, 1H), 3.73 (m, 2H), 3.33-3.24 (m, 2H), 3.16-2.99 (m, 2H),2.78 (br., 1H), 2.34-1.50 (m, 10H), 1.27 (s, 9H), 1.15 (m, 3H); ESI-MS563 (M+H), 585 (M+Na).

Example 15 Preparation ofN-[(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)methyl]-N-methylnaphthalene-1-sulfonamide

N-[(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)methyl]-N-methylnaphthalene-1-sulfonamide(44.2 mg, 75%) was obtained as a solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (30mg, 0.10 mmol),N-methyl-N-(piperidin-4-ylmethyl)naphthalene-1-sulfonamide (31.8 mg, 0.1mmol), and polymer supported-triacetoxyborohydride (200 mg, 0.6 mmol)following the procedure in example 1. ¹H NMR (400 MHz, CDCl₃), δ 8.71(d, 1H, J=8.1 Hz), 8.16 (d, 1H, J=7.3 Hz), 8.09 (d, 1H, J=8.0 Hz), 7.95(d, 1H, J=7.9 Hz), 5.42 (d, 1H, J=10.8 Hz), 4.77 (d, 1H, J=10.8 Hz),4.46-4.09 (m, 3H), 3.25-0.85 (m, 17H), 1.34 (s, 9H); ESI-MS 592 (M+H).

Example 16 Preparation ofN-[(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)methyl]naphthalene-2-sulfonamide

N-[(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)methyl]naphthalene-2-sulfonamide(26.4 mg, 46%) was obtained as a solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (30mg, 0.10 mmol), N-(piperidin-4-ylmethyl)naphthalene-2-sulfonamide (30.4mg, 0.1 mmol), and polymer supported-triacetoxyborohydride (200 mg, 0.6mmol) following the procedure in example 1. ¹H NMR (300 MHz, CDCl₃), δ8.40 (s, 1H), 7.98-7.87 (m, 3H), 7.81 (dd, 1H, J=8.7, 1.7 Hz), 7.67-7.57(m, 2H), 7.40-7.25 (m, 5H), 5.38 (d, 1H, J=10.9 Hz), 5.15 (br., 1H),4.75 (d, 1H, J=11.0 Hz), 4.08 (m, 1H), 3.21-2.92 (m, 3H), 2.81 (br.,2H), 2.48 (m, 1H), 2.33-2.11 (m, 3H), 2.09-1.90 (m, 4H), 1.75-1.62 (m,2H), 1.61-1.35 (m, 3H), 1.25 (s, 9H); ESI-MS 578 (M+H).

Example 17 Preparation ofN-(cyclopropylmethyl)-N-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)pyrimidin-2-amine

N-(cyclopropylmethyl)-N-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)pyrimidin-2-amine(29.1 mg, 58%) was obtained as a solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (30mg, 0.10 mmol), N-(cyclopropylmethyl)-N-piperidin-4-ylpyrimidin-2-amine(26.9 mg, 0.1 mmol), and polymer supported-triacetoxyborohydride (200mg, 0.6 mmol) following the procedure in example 1. ¹H NMR (300 MHz,CDCl₃), δ 8.26 (d, 2H, J=4.7 Hz), 7.42-7.27 (m, 5H), 6.44 (t, 1H, J=4.7Hz), 5.41 (d, 1H, J=10.8 Hz), 4.77 (d, 1H, J=11.0 Hz), 4.57 (m, 1H),4.12 (m, 1H), 3.37 (d, 2H, J=6.5 Hz), 3.23-3.08 (m, 3H), 2.58 (br., 1H),2.42-2.20 (m, 5H), 2.15-2.00 (m, 4H), 1.83-1.70 (m, 2H), 1.27 (s, 9H),1.10 (m, 1H), 0.45 (m, 2H), 0.32 (m, 2H); ESI-MS 506 (M+H), 528 (M+Na).

Example 18 Preparation ofN-allyl-N-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)pyridin-2-amine

N-allyl-N-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)pyridin-2-amine(36.0 mg, 73%) was obtained as a solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (30mg, 0.10 mmol), N-allyl-N-piperidin-4-ylpyridin-2-amine (25.4 mg, 0.1mmol), and polymer supported-triacetoxyborohydride (200 mg, 0.6 mmol)following the procedure in example 1. ¹H NMR (400 MHz, CDCl₃), δ 8.07(m, 1H), 7.42-7.27 (m, 6H), 6.51 (dd, 1H, J=6.8, 5.2 Hz), 6.39 (d, 1H,J=8.5 Hz), 5.80 (m, 1H), 5.41 (d, 1H, J=11.0 Hz), 5.16-5.06 (m, 2H),4.76 (d, 1H, J=10.9 Hz), 4.12 (m, 1H), 3.89 (s, 2H), 3.20-3.02 (m, 3H),2.55 (br., 1H), 2.38-166 (m, 12H), 1.27 (s, 9H); ESI-MS 491 (M+H), 513(M+Na).

Example 19 Preparation of(1R,5S)-N-allyl-8-{2-[3-(2,2-dimethylpronanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}-N-phenyl-8-azabicyclo[3.2.1]octan-3-amine

(1R,5S)-N-allyl-8-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}-N-phenyl-8-azabicyclo[3.2.1]octan-3-amine(31.2 mg, 60%) was obtained as a solid from3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (30mg, 0.10 mmol),(1R,5S)-N-allyl-N-phenyl-8-azabicyclo[3.2.1]octan-3-amine (27.9 mg, 0.1mmol), and polymer supported-triacetoxyborohydride (200 mg, 0.6 mmol)following the procedure in example 1. ¹H NMR (400 MHz, CDCl₃), δ7.43-7.25 (m, 7H), 7.03 (m, 1H), 6.96 (m, 1H), 5.68 (m, 1H), 5.41 (d,1H, J=10.7 Hz), 5.05 (d, 1H, J=10.3 Hz), 4.98 (d, 1H, J=16.9 Hz), 4.89(d, 1H, J=10.9 Hz), 3.96 (m, 1H), 3.78 (m, 1H), 3.71 (d, 2H, J=6.6 Hz),3.62-3.30 (m, 4H), 2.88-1.60 (m, 13H), 1.26 (m, 6H); ESI-MS 516 (M+H),538 (M+Na).

Example 20 Preparation ofN-(tert-butyl)-4-chloro-2-fluoro-5-[(6-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl]-6-phenyl-1,3-oxazinan-3-yl)carbonyl]benzenesulfonamide

Preparation ofN-(tert-butyl)-4-chloro-2-fluoro-5-{[6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-3-yl]carbonyl}benzenesulfonamide.A solution of1-amino-5{[tert-butyl(dimethyl)silyl]oxy}-3-phenylpentan-3-ol (278 mg,0.9 mmol) and p-formaldehyde (300 mg, 10 mmol) in 9 mL MeOH was heatedunder reflux for 90 min. A 2 mL aliquot (0.2 mmol) was removed,filtered, and concentrated in vacuo. The residue was redissolved in 0.5mL DMF and 1 mL CH₂Cl₂ and to this solution was added5-[(tert-butylamino)sulfonyl]-2-chloro-4-fluorobenzoic acid (62 mg, 0.2mmol), diisopropylethylamine (70 μL, 0.4 mmol) and HATU (114 mg, 0.3mmol). After 5h, saturated aqueous NaHCO₃ was added, and the aqueouslayer was extracted with CHCl₃. The organic layers were pooled, dried(Na₂SO₄), concentrated and purified by chromatography (4:1 hex:EtOAc) toprovideN-(tert-butyl)-5-{[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-phenyl-1,3-oxazinan-3-yl]carbonyl}-4-chloro-2-fluorobenzenesulfonamide,which was used without further purification. The crudeN-(tert-butyl)-5-{[6-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-phenyl-1,3-oxazinan-3-yl]carbonyl}-4-chloro-2-fluorobenzenesulfonamidewas stirred in a solution of 1 M TBAF in THF for 1.5h, then washed withsaturated aqueous NaHCO₃ and purified by chromatography (2:1 EtOAc:hex)to provideN-(tert-butyl)-4-chloro-2-fluoro-5-{[6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-3-yl]carbonyl}benzenesulfonamide(25.2 mg, 25%) as a clear oil. ¹H NMR (400 MHz, CDCl₃), δ 8.03 (d, 0.5H,J=7.3 Hz, rotamer), 7.70 (d, 0.5H, J=7.3 Hz, rotamer), 7.46-7.30 (m,6H), 5.81 (d, 0.5H, J=10.4 Hz, rotamer), 4.98 (m, 0.5H, rotamer), 4.88(m, 1H), 4.72-4.48 (m, 3H), 3.15 (m, 1H), 2.96 (m, 1H), 2.52-1.73 (m,5H), 1.24 (m, 9H, rotamers); ESI-MS 497 (M−H).

To a 0° C. solution ofN-(tert-butyl)-4-chloro-2-fluoro-5-{[6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-3-yl]carbonyl}benzenesulfonamide(25.2 mg, 0.05 mmol) in dimethyl sulfoxide (71 μL, 1 mmol),diisopropylethylamine (53 μL, 0.30 mmol) and 1 mL CH₂Cl₂ was addedSO₃.pyr in one portion. The reaction mixture was stirred for 2h at 0°C., saturated aqueous NaHCO₃ was added, and the aqueous layer wasextracted with CHCl₃. After evaporation, the resultant crudeN-(tert-butyl)-4-chloro-2-fluoro-5-{[6-(2-oxoethyl)-6-phenyl-1,3-oxazinan-3-yl]carbonyl}benzenesulfonamidewas obtained and used in the next step without further purification.

N-(tert-butyl)-4-chloro-2-fluoro-5-[(6-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-6-phenyl-1,3-oxazinan-3-yl)carbonyl]benzenesulfonamide(25.3 mg, 70%) was obtained as a white solid from the above crudeN-(tert-butyl)+chloro-2-fluoro-5-{[6-(2-oxoethyl)-6-phenyl-1,3-oxazinan-3-yl]carbonyl}benzenesulfonamide,1-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazoledihydrochloride (18.6 mg, 0.05 mmol), diisopropylethylamine (18 μL, 0.10mmol) and sodium triacetoxyborohydride (16 mg, 0.08 mmol) following theprocedure in example 1. ¹H NMR (400 MHz, CDCl₃), δ 8.03 (d, 0.5H, J=7.1Hz, rotamer), 7.72 (d, 0.5H, J=7.3 Hz, rotamer), 7.65 (m, 1H), 7.45-7.39(m, 2H), 7.37-7.28 (m, 5H), 7.20-7.11 (m, 2H), 5.73 (d, 0.5H, J=10.4ZHz, rotamer), 5.04-4.96 (m, 1H), 4.75-4.44 (m, 3.5H, rotamers),3.42-3.13 (m, 3H), 2.63-2.54 (m, 5H), 2.52-1.86 (m, 10H), 1.74-1.63(br., 2H), 1.29-1.20 (m, 9H, rotamers); ESI-MS 722 (M+H).

Those skilled in the art will appreciate such an example as a teachingof the scope of the present invention.

Preparation of tert-butyl(dimethyl)[(3-phenylbut-3-enyl)oxyl]silane

3-phenylbut-3-en-1-ol was prepared according to the literaturereference: Omaka et al. Org. Lett. 2002, 4,1667.

To a 0° C. solution of 3-phenylbut-3-en-1-ol (1.0 g, 6.7 mmol) and Et₃N(0.59 mL, 8.1 mmol) in 7 mL DMF was added TBSCI (1.2 g, 8.1 mmol). Afterstirring for 4h at 0° C., the reaction mixture was diluted with 4:1EtOAc:hex and washed with water and chromatographed (5% EtOAc in hex) toprovide tert-butyl(dimethyl)[(3-phenylbut-3-enyl)oxy]silane (794 mg,45%) as a clear oil: ¹H NMR (400 MHz, CDCl₃), δ 7.43-7.40 (m, 2H),7.35-7.30 (m, 2H), 7.26 (m, 1H), 5.34 (d, 1H, J=1.5 Hz), 5.10 (m, 1H),3.71 (t, 2H, J=7.1 Hz), 2.74 (td, 2H, J=7.1, 1.0 Hz), 0.87 (s, 9H), 0.00(s, 6H); ESI-MS 263 (M+H).

Preparation of tert-butyl4-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-2-phenylbutyl(2-hydroxyethyl)carbamate

To a solution of tert-butyl(dimethyl)[(3-phenylbut-3-enyl)oxy]silane(526 mg, 2.0 mmol) and 4-methylmorpholine N-oxide (1.15 mL of a 60%solution in water, 5.9 mmol) in 3 mL acetone and 0.75 mL pH 7 buffer wasadded OsO₄ (0.17 mL of a 4% solution in water, 0.03 mmol) and thereaction mixture was stirred for 24h. Saturated aqueous Na₂S₂O₃ wasadded and stirred for 30 min and the mixture was then diluted withEtOAc, and washed with saturated aqueous NaHCO₃, brine, dried (Na₂SO₄),and passed through a short silica plug to afford4-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylbutane-1,2-diol as a clearoil that was used without further purification: ¹H NMR (400 MHz, CDCl₃),δ 7.45-7.41 (m, 2H), 7.39-7.34 (m, 2H), 7.27 (m, 1H), 4.88 (s, 1H), 3.77(ddd, 1H, J=10.3, 4.1, 3.6 Hz), 3.67 (ddd, 1H, J=11.1, 8.4, 1.2 Hz),3.62-3.54 (m, 2H), 2.51 (dd, 1H, J=8.6, 4.8 Hz), 2.41 (ddd, 1H, J=14.8,11.3, 4.2 Hz), 1.91 (ddd, 1H, J=14.8, 3.3, 2.7 Hz), 1.55 (s, 1H), 0.88(s, 9H), 0.01 (s, 3H), −0.04 (s, 3H).

To a solution of the above4-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylbutane-1,2-diol in 2 mLpyridine was added p-toluenesulfonyl chloride (573 mg, 3.00 mmol). Afterstirring the reaction mixture for 24h, water was added and the solutionwas extracted with EtOAc. The organic layers were pooled and washed withbrine, dried (Na₂SO₄), evaporated and redissolved in 5 mL CH₃CN. To thissolution was added ethanolamine (0.61 mL, 10.0 mmol) and the reactionmixture was heated at 100° C. for 24h. After dilution with EtOAc, themixture was washed with brine, dried (Na₂SO₄), evaporated andredissolved in 2 mL CH₂Cl₂. To this was added Et₃N (0.40 mL, 2.9 mmol),and di-tert-butyl dicarbonate (570 mg, 2.6 mmol) and the reactionmixture was stirred for 24 h. Water was added and the solution asextracted with CH₂Cl₂ and purified by chromatography (3:1 hex:EtOAc) toafford tert-butyl4-{[tert-butyl(dimethyl)silyl]oxy}2-hydroxy-2-phenylbutyl(2-hydroxyethyl)carbamate(773 mg, 88%) as a clear oil: ¹H NMR (400 MHz, CDCl₃), δ 7.48 (m, 1H),7.40 (m, 1H), 7.37-7.31 (m, 2H), 7.25 (m, 1H), 3.99 (d, 1H, J=14;1 Hz),3.88-3.59 (m, 4H), 3.50-3.41 (m, 2H), 3.27 (m, 1H), 3.14 (m, 1H),2.34-2.13 (m, 2H), 2.06 (m, 1H), 1.45 (s, 9H), 0.83 (s, 9H), −0.05 (s,3H), −0.13 (s, 3H).

Preparation of tert-butyl2-(2-hydroxyethyl)-2-phenylmorpholine-4-carboxylate

To a solution of tert-butyl4-{[tert-butyl(dimethyl)silyl]oxy}-2-hydroxy-2-phenylbutyl(2-hydroxyethyl)carbamate(770 mg, 1.7 mmol) and triphenylphosphine (551 mg, 2.1 mmol) in 8 mLtoluene was added diethyl azodicarboxylate (0.96 mL of a 40% solution intoluene, 2.1 mmol) and the reaction was stirred for 24 h. Afterevaporation, the residue was chromatographed (10% EtOAc/hex) to affordtert-butyl2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-phenylmorpholine-4-carboxylateas an oil, which was used without further purification. ESI-MS 422(M+H).

The above tert-butyl2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-phenylmorpholine-4-carboxylatewas stirred in 4 mL of a 1 M solution of tetrabutylammonium fluoride inTHF for 1 h at room temperature. The reaction mixture was then dilutedwith CHCl₃, washed with saturated aqueous NaHCO₃, and purified (1:1hex:EtOAc) to provide tert-butyl2-(2-hydroxyethyl)-2-phenylmorpholine-4-carboxylate (449 mg, 83%) as anoil: ¹H NMR (400 MHz, CDCl₃), δ 7.47-7.41 (m, 2H), 7.40-7.35 (m, 2H),7.28 (m, 1H), 4.34 (m, 1H), 3.77-3.63 (m, 2H), 3.63-3.48 (m, 3H), 3.35(m, 1H), 3.17 (m, 1H), 2.08 (m, 1H), 1.89 (m, 1H), 1.50-1.37 (br., 9H);ESI-MS 330 (M+Na).

Preparation of tert-butyl2-(2-oxoethyl)-2-phenylmorpholine-4-carboxylate

To a 0° C. solution of tert-butyl2-(2-hydroxyethyl)-2-phenylmorpholine-4-carboxylate (428 mg, 1.4 mmol),dimethyl sulfoxide (4.0 mL, 56.4 mmol) and diisopropylethylamine (1.3mL, 7.2 mmol) in 8 mL CH₂Cl₂ was added SO₃.pyr (1.4 g, 8.8 mmol) and thereaction mixture was stirred for 2h. After the addition of saturatedaqueous NaHCO₃, the solution was extracted with CHCl₃, and passedthrough a plug of silica gel flushing with 2:1 hex:EtOAc to providetert-butyl 2-(2-oxoethyl)-2-phenylmorpholine-4-carboxylate (226 mg, 53%)as a clear oil. ¹H NMR (400 MHz, CDCl₃), δ 9.60 (br. s, 1H), 7.54-7.44(br., 2H), 7.42-7.37 (m, 2H), 7.30 (m, 1H), 4.25-4.01 (br., 1H),3.80-3.23 (m, 5H), 3.00-2.81 (m, 2H), 2.73 (br., 1H), 1.47 (br., 9H);ESI-MS 328 (M+H).

Preparation of tert-butyl2-{2-[(1R,5S-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholine-4-carboxylate

To a solution of tert-butyl2-(2-oxoethyl)-2-phenylmorpholine-4-carboxylate (226.1 mg, 0.74 mmol),1-[(1R,5S)₈-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazoledihydrochloride (272.7 mg, 0.74 mmol) and diisopropylethylamine (0.27mL, 1.48 mmol) in 3 mL CH₂Cl₂ was added sodium triacetoxyborohydride(235.4 mg, 1.11 mmol) and the reaction mixture was stirred for 2h atroom temperature. After evaporation, the residue was chromatographed (5%(2M NH₃/MeOH) in CHCl₃) to provide tert-butyl2-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholine-4-carboxylate(329.9 mg, 84%) as an off-white foam: ¹H NMR (400 MHz, CDCl₃), δ 7.65(m, 1H), 7.49-7.40 (br., 2H), 7.39-7.34 (m, 2H), 7.31 (m, 1H), 7.27 (m,1H), 7.19-7.11 (m, 2H), 4.75-4.16 (m, 2H), 3.76-3.47 (m, 3H), 3.40-3.13(m, 4H), 2.58 (s, 3H), 2.46-2.32 (m, 2H), 2.17-1.82 (m 8H), 1.63 (m,2H), 1.53-1.40 (br., 9H); ESI-MS 531 (M+H), 553 (M+Na).

Preparation of2-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl)}-1H-benzimidazole

To a solution of tert-butyl2-2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholine-4-carboxylate(330 mg, 0.62 mmol) in 5 mL CHCl₃ was added 0.8 mL of a solution of 4NHCl in dioxane. After stirring at room temperature for 2 h, another 3 mL4N HCl in dioxane was added and the mixture was heated at 40° C. for 90min. The solution was then evaporated and dried in vacuo to provide2-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazoletrihydrochloride, which was used without further purification. ESI-MS431 (M+H).

Example 21 Preparation of2,2-dimethyl-3-(2-{2-[(1R,5S-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholin-4-yl)-3-oxopropan-1-ol

To a stirred solution of2-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazoletrihyrdochloride (59.3 mg, 0.10 mmol), 3-hydroxy-2,2-dimethylpropanoicacid (18 mg, 0.15 mmol), and diisopropylethylamine (70 μL, 0.40 mmol) in1 mL DMF was added HATU (57 mg, 0.15 mmol). The resulting mixture wasstirred at ambient temperature for 24 h and then diluted with methylenechloride and washed with saturated aqueous NaHCO₃. The organic phase wasdried (Na₂SO₄), concentrated by evaporation, and purified bychromatography (5% (2M NH₃/MeOH) in CHCl₃) to afford2,2-dimethyl-3-(2-{2-[(1R,5S)-3(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholin-4-yl)-3-oxopropan-1-ol(29.3 mg. 55%) as amorphous solid. ¹H NMR (400 MHz, CDCl₃), δ 7.65 (m,1H), 7.44-7.26 (m, 6H), 7.19-7.10 (m, 2H), 4.80 (br., 1H), 4.69 (m, 1H),3.75-3.37 (m, 8H), 3.35-3.16 (m, 3H), 2.58 (s, 3H), 2.46-2.34 (m, 2H),2.13-1.84 (m, 8H), 1.68-1.59 (m, 2H), 1.23 (s, 3H), 1.02 (s, 3H); ESI-MS531 (M+H), 553 (M+Na).

Example 22 Preparation of4-chloro-N-isopropyl-3-[(2-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholin-4-yl)carbonvl]benzenesulfonamide

4-chloro-N-isopropyl-3-[(2-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholin-4-yl)carbonyl]benzenesulfonamide(33.2 mg, 48%) was obtained from2-chloro-5-[(isopropylamino)sulfonyl]benzoic acid (38 mg, 0.15 mmol),2-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazoletrihyrdochloride (59.3 mg, 0.10 mmol) and HATU (57 mg, 0.15 mmol)following the procedure outlined in example 20. ¹H NMR (400 MHz, CDCl₃),δ 7.82-7.72 (m, 1H), 7.64 (m, 1H), 7.57-7.47 (m, 3H), 7.46-7.26 (m, 5H),7.20-7.09 (m, 2H), 5.26-5.15 (m, 1H, rotamers), 5.06 (m, 0.5H, rotamer),4.86 (m, 0.5H, rotamer), 4.72 (m, 1H), 3.72-3.20 (m, 7H), 3.05 (m, 1H),2.60 (s, 3H), 2.49-1.57 (m, 11H), 1.12-1.01 (m, 6H, rotamers); ESI-MS690 (M+H).

Example 23 Preparation of4-chloro-2-fluoro-5-[(2-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholin-4-yl)carbonyl]benzenesulfonamide

4-chloro-2-fluoro-5-[(2-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholin-4-yl)carbonyl]benzenesulfonamide(16.6 mg, 25%) was obtained from5-(aminosulfonyl)-2-chloro-4-fluorobenzoic acid (38 mg, 0.15 mmol),2-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazoletrihyrdochloride (59.3 mg, 0.10 mmol) and HATU (57 mg, 0.15 mmol)following the procedure outlined in example 20. ¹H NMR (400 MHz, CDCl₃),δ 7.83 (m, 0.3H, rotamer), 7.66-7.49 (m, 2.7H, rotamers), 7.45-7.26 (m,5H), 7.20-7.10 (m, 3H), 5.17 (m, 0.5H, rotamer), 4.92 (m, 0.5H,rotamer), 4.72 (m, 1H), 5.17 (m, 0.5H, rotamer), 4.92 (m, 0.5H,rotamer), 4.72 (m, 1H), 3.73-3.46 (m, 2H), 3.42-3.19 (m, 4H), 3.06 (m,1H), 2.60 (m, 3H, rotamers), 249-2.37 (m, 2H), 2.17-1.79 (m, 7H),1.71-1.61 (m, 2H); ESI-MS 666 (M+H).

Example 24 Preparation of1-((1R,5S)-8-{2-[4-(2,2-dimethylpropanoyl)-2-phenylmorpholin-2-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole

To a solution of2-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazoletrihyrdochloride (65 mg, 0.11 mmol) and Et₃N (0.08 mL, 0.55 mmol in 1 mLCH₂Cl₂ was added trimethylacetyl chloride (0.02 mL, 0.17 mmol), and thereaction was stirred for 24 h. After washing with saturated aqueousNaHCO₃, the organic phase was isolated, dried (Na₂SO₄), concentrated andchromatographed (5% (2M NH₃/MeOH) in CHCl₃) to afford1-((1R,5S)-8-{2-[4-(2,2-dimethylpropanoyl)-2-phenylmorpholin-2-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole(61 mg, quant.) as a film: ¹H NMR (400 MHz, CDCl₃), δ 7.68 (m, 1H),7.45-7.40 (m, 2H), 7.38-7.27 (m, 3H), 7.19-7.11 (m, 2H), 4.77-4.63 (m,2H), 3.76-3.54 (m, 4H), 3.40-3.20 (m, 3H), 2.59 (s, 3H), 2.48-2.36 (m,2H), 2.15-1.85 (m, 8H), 1.69-1.59 (m, 2H), 1.19 (s, 9H); ESI-MS 515(M+H).

Biological Data

The following definitions apply: IC₅₀ Concentration of compound thatdisplaces 50% of radioligand PIC₅₀ The determined IC₅₀ value expressedas −log10(IC₅₀)CC-Chemokine Receptor-5 Binding by Scintillation Proximity Assay (CCR5SPA)

Scintillation Proximity Assay for the Human CC-Chemokine Receptor, CCR-5

This protocol describes a high-throughput screen using SPA binding toidentify compounds that inhibit binding of ¹²⁵I-MIP1α to the human CCR5chemokine receptor.

CCR5 is a G protein-coupled receptor that binds the natural chemokineligands, MIP1α, MIP1β and RANTES. CCR5 acts as a co-receptor with CD4for entry of HIV-1 into human T-cells and monocytes. Chemokines alsoplay a role in acute and chronic inflammatory processes. Chemokines aresoluble proteins produced and released by a wide variety of cell typesduring the initial phase of a host response to a forgein substanceentering the body.

Human CCR5 receptors were expressed in Chinese Hamster Ovary (CHO)cells, registration # 12025. Cells were grown in suspension and a 50 to80 ml CCR5 cell pellet was prepared. Membrane preparation: 1) Weighpellet; 2)Prepare an ice-cold 50 mM HEPES buffer, containing 0.0025mg/ml Pefabloc, 0.0001 mg/ml Pepstatin A, 0.0001 mg/ml Leupeptin, 0.0001mg/ml Aprotinin (protease inhibitor cocktail), pH 7.4; 3) Homogenizepellet in 5 volumes of HEPES buffer; 4) Homogenize again with a glasshomogenizer 10 to 20 strokes; 5) Centrifuge homogenate at 18,000 rpm ina F28/36 rotor using a Sorvall RC26 PIUS refrigerated Centrifuge for 30minutes; 6) Discard supernatant and resuspend pellet in 3 volumes ofHEPES buffer; 7) Homogenize and centrifuge again using steps 4-6, 2 moretimes; 8) Reweigh pellet and homogenize in 3× weight-to-volume of HEPESbuffer; 9) Aliquot 0.5 to 1.5 ml of the membrane preparation into smallvials and store at −80 degrees Centigrade; 10) Determine the proteinconcentration of the membrane preparation using the Bio-Rad or BCAmethod; 11) The membrane homogenate will need to be characterized forthe assay conditions a.) Protein concentration; b.) Optimalprotein-to-bead ratio in SPA; and c.) Saturation curve to determine Kdand Bmax in SPA

The saturation curve binding experiment is performed by adding varyingamounts of [¹²⁵I]MIP1α (0-8.5 nM to membranes and beads inconcentrations chosen from the optimal protein/bead ratio. The data isanalyzed using a non-linear curve-fitting program. The K_(d) and Bmaxare derived from the curve.

Bacitracin 50 mg/ml is dissolved in deionized water, brought to a boilfor 5 minutes (to destroy protease activity) and cooled. Prepared 1 mlaliquots and store at −80° C.

Protease inhibitor cocktail is prepared by dissolving 25 mg/ml ofPefabloc, 1 mg/ml of Leupeptin, 1 mg/ml of Aprotinin and 1 mg/ml ofPepstatin A in 100% DMSO. The cocktail can be aliquoted and storedfrozen at −20° C. until needed.

Sigmacote: Any reagent bottles and reservoirs that come in contact withthe radioligand are treated with Sigmacote to reduce sticking. Rinsecontainers with undiluted Sigmacote; rinse with deionized water severaltimes, and allow to air dry before using.

Color Quench Assay-[¹²⁵I] SPA PVT color quench kit, Cat. No. RPAQ 4030,Amersham Ltd. A color quench curve is generated for each PackardTopCount and is stored in each counting protocol specific for the assay.This is done to prevent colored compounds from quenching thescintillation counts.

Compounds Preparation:

Compounds for a single concentration determination (One Shots) aredelivered in 96 well Packard Optiplates containing 1 μl of compound in100% DMSO in columns A1-H10 (80 compounds/plate). Column A11 to H11 isused for total binding (Bo) (vehicle-5 μl of the appropriate DMSOconcentration) and column A12 to D12 is used for determination ofnonspecific binding. No further preparation is required.

Compounds for concentration-response curves (10 points) are delivered in96-Packard Optiplates containing 1 μl of compound in 100% DMSO incolumns A1-H10. A 10-point concentration-response curve is desired foreach compound with a starting high concentration of 30 μM (in the assauyfinal). Column A11 to H11 is used for total binding (Bo) (vehicle-5 μlof the appropriate DMSO concentration) and column A12 to D12 is used fordetermination of nonspecific binding. No further preparation is required

Materials:

-   1 M HEPES, pH 7.4, Gibco, Cat. No. 15360-080-   Bacitracin, Sigma Catalog. Number. B-0125-   Bovine Serum Albumin, Sigma, Cat. No. A-7888-   MgCl₂, J. T. Baker 2444-01-   CaCl₂, Sigma, Cat. No. C5080-   MIP1α, Peprotech, Cat. No. 300-08-   Sigmacote, Sigma, Cat. No. SL2-   Scintillation Proximity Beads, Wheat Germ Agglutinin, Amersham, Cat    No. RPNQ 0001-   [¹²⁵I]MlP1α, NEN (#NEX298)-   Packard 96 well flat-bottom Optiplate, Cat. No. 6005190-   Falcon 96 well round-bottom plate, Cat. No. 3077-   TOPSEAL-S, Packard, Cat. No. 6005161-   Dimethyl Sulfoxide, EM Science, Cat. No. MX1458-6-   Siliconized Pipette tips, Accutip, volume 200-1300 uL, Cat. No.    P5048-85-   Siliconized Pipette tips, Bio Plas, Inc., volume 1-200 uL, Cat. No.    60828-908-   Reagent Reservoir, Elkay, Cat. No. 175-RBAS-000    Assay Buffer Preparation:

50 mM HEPES buffer pH 7.4, 1 mM CaCl₂, 5 mM MgCl2(this can be made aheadas a 100× stock), 1% BSA, 0.5 mg/ml Bacitracin, Protease inhibitorCocktail (see preparation above) 100 uL/100 ml, DMSO is added to equal afinal concentration of 2% per well (includes compound % DMSO) if needed.

Experimental Details:

[¹²⁵I]MIP1α Preparation:

Prepared radioligand dilutions in container treated with Sigmacote

Reconstitute each 50 μCi vial with 0.5 ml of deionized water and storeat 4° C.

Specific Activity=2,000 Ci/mmol

Add˜60,000 cpm (0.17 nM) to each assay well in 50 uL

Bo:

Make a 20% DMSO solution and add 5 uls of this to each well in colA11-H11. This gives a final 2% DMSO concentration for the well whenadded to the 1% in the assay buffer.

NSB:

Make a stock dilution of MIP1α at 100 uM using deionized water; aliquotand freeze. Dilute the MIP-1α stock solution to a concentration of 2 μMin the same 20% DMSO solution used above and add 5 μl to the wells incolumn A12 to D12 to give a final assay concentration of 100 nM. Preparethis in a Sigmacote-treated container

Membrane and SPA Bead Preparation—

The final assay concentration for the membrane is 15 μg per well. SPAbeads are prepared by adding 5 ml of assay buffer to a 500 mg vial. Thefinal concentration of SPA beads in the assay is 0.25 mg/well. Membranesand beads are premixed as a 1:1 (membrane:bead) mixture and maintainedat mixture at 4° C. with constant stirring. 50 μl of the mixture isadded to each assay well. After all reagents have been added to theplates (total assay volume 100 μl), shake plates for 4 hours at roomtemperature. After 4 hours, place the plates on the TopCount in a countthe plates on the TopCount for 30 sec per well using an appropriateprogram (i.e., one with a quench curve established for the conditions ofthe assay.

Data Reduction:

Data reduction is performed using the Microsoft Excel Addins Robofit orRobosage.

For single concentration assays (One Shots), the result of each testwell is expressed as % inhibition using the following formula:100*(1-(U1-C2)/(C1-C2)). Where U1 is the unknown sample in cpm observedin a particular well, C1 is the average of column 12 cpm observed in theabsence of any added inhibitor, and C2 is the average of column 11 cpmobserved in the presence of 1 μM of MIP1α.

For concentration-response assays, the result of each test well isexpressed as % B/Bo (% total specific binding) using the followingformula: 100*(U1-C2)/C1-C2).

Curves were generated by plotting the % B/Bo versus the concentrationand the IC₅₀ is derived using the equation y=Vmax*(1−(xˆn/(kˆn+xˆn))).

Controls and Standards:

Each plate contains 12 wells of total binding (column A11-H11). Thecpm/well are averaged and are used in data reduction as value C1.Eachplate also contains 4 wells of non-specific binding (wells A12-D12). Thecounts of these wells are averaged and used in data reduction as valueC2.

A standards plate is included in each experiment. This plate contains a14-point concentration-response curve (in triplicate) for the standardcompound MIP1α at a starting concentration of 1 μM. The averagehistorical pK₁ obtained with MlP1α is 7.6.

The relevant biological response field for a single concentration (OneShots) is % inhibition. Inhibition values of >40 or >50% were consideredpositive responses.

The relevant biological response field for a concentration-responseexperiment is pK₁ HOS Assay (Also referred to as HOS-LTR-LuciferaseAssay)

Materials

-   DMEM (GibcoBRL # 10564-011)-   Trpsin-EDTA (GibcoBRL #25300-054)-   Heat inactivated Fetal Bovine Serum (FBS) (Hyclone # SH30070.03)-   96-well, black-walled, clear-bottom, tissue culture-treated plates    (Costar # 3904)-   96-well, clear-walled, clear-bottom tissue culture-treated plates    (Costar # 3598)-   Phosphate Buffered Saline (PBS) (GibcoBRL #14190-144)-   Dimethyl Sulfoxide (DMSO) (Sigma # D2650)-   Luclite Luciferase Reporter assay (Packard #6016911)-   HOS-CD4.CCR5-LTR-Luciferase (Bioresource Registration # 21164):    Human Osteosarcoma cell line engineered to overexpress human CD4 and    human OCR5 (AIDS Repository cat# 3318) stabily transfected with    HIV-1-LTR-Luciferase reporter.

Advanced Preparation

Growth and Maintenance of the HOS-CD4.CCR5-LTR-Luciferase cell line:

The cells were propagated in DMEM containing 2% FBS. Cells were split bystandard trypsinization when confluency reached 80% (roughly every 2 to3 days).

Titering of Virus Stocks:

HIV-1 virus stocks were titered in the assay system in order to obtainan estimate of the number of infectious particles per unit volume(described as RLU/ml). Virus stocks were diluted into DMEM containing 2%FBS and assayed as described in the “procedure” section below.

Procedure

Black-walled 96-well tissue culture plates were seeded withHOS-CD4.CCR5-LTR-Luciferase @ 0.6 to 1.2×10³ cells per well in 50 ulDMEM containing 2% FBS and placed in a humidified incubator @ 37° C., 5%CO₂ overnight. The following day, test compounds were titrated 4-fold at2× the final concentration in DMEM+2% FBS+0.2% DMSO. 50 μl of titratedcompound was transferred to the HOS cells and the plates were placed ina humidified incubator at 37° C., 5% CO₂ for 1 hr. An additional 60 ulof 2× titrated compound was transferred to a clear-walled 96-well tissueculture plate and 60 ul of HIV (diluted to appropriate m.o.i.) was addedto each well and thoroughly mixed. 100 ul of the HIV/compound mixturewas transferred to the black-walled plates containing 100 ul ofcells/compound. The plates were placed in a humidified incubator at 37°C., 5% CO₂for 72 hr Following the 72 hour incubation, 150 ul ofsupernatant was removed and 50 ul of reconstituted LUCLITE (kit reagent)was added to each well. Each plate was sealed and read in a Topcount(Packard) luminometer at 1s/well.

Data Reduction

Relative Light Units (RLU) were expressed as % control (RLU at drug []/RLU no drug)*100=% Control

IC₅₀ values were determined by any one of the following four nonlinearregression models:

-   -   y=Vmax*(1−(xˆn/(Kˆn+xˆn)))+Y2    -   y=Vmax*(1−(xˆn/(Kˆn+xˆn)))    -   y=Vmax*(1−(x/(K+x)))+Y2    -   y=Vmax*(1−(x/(K+x)))        Where: K is IC₅₀, Y2 is baseline, and N is Hill Coefficient

Each of the compounds of the present invention is believed to provide apIC₅₀ value of at least 5 when tested in each of the above-describedassays.

Test compounds are employed in free or salt form.

All research complied with the principles of laboratory animal care (NIHpublication No. 85-23, revised 1985) and GlaxoSmithKline policy onanimal use.

Although specific embodiments of the present invention have beenillustrated and described in detail, the invention is not limitedthereto. The above detailed description of preferred embodiments isprovided for example only and should not be construed as constitutingany limitation of the invention. Modifications will be obvious to thoseskilled in the art, and all modifications that do not depart from thespirit of the invention are intended to be included within the scope ofthe appended claims.

1. A compound of formula (I)

or a pharmaceutically acceptable derivative thereof, wherein: X is aC₁₋₅ alkylene chain, wherein said X is optionally substituted by one ormore ═O, ═S, —S(O)_(t)—, alkyl, or halogen and wherein said C₁₋₅alkylene chain may optionally have 0-3 heteroatoms selected from oxygen,phosphorus, sulfur, or nitrogen; Ring A is a saturated, partiallysaturated or aromatic 3-7 monocyclic or 8-10 membered bicyclic ringhaving one ring nitrogen and 0-4 additional heteroatoms selected fromoxygen, phosphorus, sulfur, or nitrogen; Ring B has an oxygen atom inaddition to the depicted nitrogen; R¹ is alkyl optionally substituted byone or more R⁷, alkenyl optionally substituted by one or more R⁷,alkynyl optionally substituted by one or more R⁷, cycloalkyl optionallysubstituted by one or more R⁸, heterocyclyl optionally substituted byone or more R⁸, heteroaryl optionally substituted by one or more R⁶, oraryl optionally substituted by one or more R⁶; or R¹ and X takentogether form a saturated, partially saturated or aromatic 5-6 memeberedring having 0-3 heteroatoms selected from oxygen, phosphorus, sulfur, ornitrogen that is fused to Ring A; each R² is independently selected fromthe group consisting of-OR⁰, —C(O)—R⁰, —S(O)₂—R⁰, —C(O)—N(R⁰)₂,—S(O)₂—N(R⁰)₂, —(CH₂)_(a)—N(R⁰)(—V_(b)—R⁺), —(CH₂)_(a)—(—V_(b)—R⁺),halogen, alkyl optionally substituted by one or more R⁷, alkenyloptionally substituted by one or more R⁷, alkynyl optionally substitutedby one or more R⁷, aryl optionally substituted by one or more R⁶,heteroaryl optionally substituted by one or more R⁶, cycloalkyloptionally substituted by one or more R⁸, and heterocyclyl optionallysubstituted by one or more R⁸; and two adjacent R²S on Ring A areoptionally taken together to form a fused, saturated, partiallysaturated or aromatic 5-6 membered ring having 0-3 heteroatoms selectedfrom oxygen, phosphorus, sulfur, or nitrogen; or two geminal R²s areoptionally taken together to form a spiro, saturated, partiallysaturated or aromatic 5-6 membered ring having 0-3 heteroatoms selectedfrom oxygen, phosphorus, sulfur, or nitrogen, said fused or spiro ringbeing optionally substituted by one or more R⁸; each a independently is0-3; each b independently is 0 or 1; V is —C(O)—, —C(O)O—, —S(O)₂—, or—C(O)—N(R⁰)—; R⁺ is alkyl, cycloalkyl, aralkyl, aryl, heteroaryl,heteroaralkyl, or heterocyclyl, wherein said R⁺ is optionallysubstituted by one or more R⁸; m is 0 or 1; n is 0-5; R³ is H, —N(R⁰)₂,—N(R⁰)C(O)R⁰, —CN, halogen, CF₃, alkyl optionally substituted by one ormore groups selected from R⁷ or —S-aryl optionally substituted by—(CH₂)₁₋₆—N(R⁰)SO₂(R⁰), alkenyl optionally substituted by one or moregroups selected from R⁷ or —S-aryl optionally substituted by—(CH₂)₁₋₆—N(R⁰)SO₂(R⁰), alkynyl optionally substituted by one or moregroups selected from R⁷ or —S-aryl optionally substituted by—(CH₂)₁₋₆—N(R⁰)SO₂(R⁰), cycloalkyl or carbocyclyl optionally substitutedby one or more R⁸, aryl optionally substituted by one or more R⁶,heteroaryl optionally substituted by one or more R⁶, or heterocyclyloptionally substituted by one or more R⁸; Y is alkyl, alkenyl, alkynyl,—(CR⁴R⁵)_(p)—, —C(O)—, —C(O)C(O)—, —C(S)—, —O—(CH₂)₀₋₄—C(O)—,—(CH₂)₀₋₄—C(O)—O—, —N(R⁰)—C(O)—, —C(O)—N(R⁰)—, —N(R⁰)—C(S)—, —S(O)_(t)—,—O—C(═N—CN)—, —O—C(═N—R⁰)—, —C(═N—CN)—O—, —C(═N—R⁰)—O—, —C(═N—CN)—S—,—S—C(═N—CN)—, —N(R⁰)—C(═N—CN)—, —C(═N—CN)—, —N(R⁰)—C[═N—C(O)—R⁰],—N(R⁰)—C[═N—S(O)_(t)—R⁰], —N(R⁰)—C(═N—OR⁰)—, —N(R⁰)—C(═N—R⁰)—, or—C(═N—R⁰)—; each R⁴ is independently H, alkyl optionally substituted byR⁷, alkenyl optionally substituted by R⁷, or alkynyl optionallysubstituted by R⁷; each R⁵ is independently selected from H, —C(O)—OR⁶,—C(O)—N(R⁰)₂, —S(O)₂—N(R⁰)₂, —S(O)₂—R⁰, aryl optionally substituted byR⁶, or heteroaryl optionally substituted by R⁶; p is 1-5; each tindependently is 1 or 2; each R⁶ is independently selected from thegroup consisting of halogen, —CF₃, —OCF₃, —OR⁰, —(CH₂)₁₋₆—OR⁰, —SR⁰,—(CH₂)₁₋₆SR⁰, —SCF₃, —R⁰, methylenedioxy, ethylenedioxy, —NO₂, —CN,—(CH₂)₁₋₆—CN, —N(R⁰)₂, —(CH₂)₁₋₆—N(R⁰)₂, —NR⁰C(O)R⁰, —NR⁰(CN),—NR⁰C(O)N(R⁰)₂, —NR⁰C(S)N(R⁰)₂, —NR⁰—CO₂R⁰, —NR⁰NR⁰C(O)R⁰,—NR⁰NR⁰C(O)N(R⁰)₂, —NR⁰NR⁰CO₂R⁰, —C(O)C(O)R⁰, —C(O)CH₂C(O)R⁰,—(CH₂)₀₋₆CO₂R⁰, —O—C(O)R⁰, —C(O)R⁰, —C(O)N(R⁰)N(R⁰)₂, —C(O)N(R⁰)₂,—C(O)N(R⁰)OH, —C(O)N(R⁰)SO₂R⁰, —OC(O)N(R⁰)₂, —S(O)_(t)R⁰, —S(O)_(t)—OR⁰,—S(O)_(t)N(R⁰)C(O)R⁰, —S(O)_(t)N(R⁰)OR⁰, —NR⁰SO₂N(R⁰)₂, —NR⁰SO₂R⁰,—C(═S)N(R⁰)₂, —C(═NH)—N(R⁰)₂, —(CH₂)₁₋₆-C(O)R⁰, —C(═N—OR⁰)—N(R⁰)₂,—O—(CH₂)₀₋₆-SO₂N(R⁰)₂, —(CH₂)₁₋₆NHC(O)R⁰, and —SO₂N(R⁰)₂ wherein the twoR⁰s on the same nitrogen are optionally taken together to form a 5-8membered saturated, partially saturated, or aromatic ring havingadditional 0-4 heteroatoms selected from oxygen, phosphorus, nitrogen,or sulfur; each R⁷ is independently selected from the group consistingof halogen, —CF₃, —R⁰, —OR⁰, —OCF₃, —(CH₂)₁₋₆—OR⁰, —SR⁰, —SCF₃,—(CH₂)₁₋₆-SR⁰, aryl optionally substituted by R⁶, methylenedioxy,ethylenedioxy, —NO₂, —CN, —(CH₂)₁₋₆—CN, —N(R⁰)₂, —(CH₂)₁₋₆—N(R⁰)₂,—NR⁰C(O)R⁰, —NR⁰ (CN), —NR⁰C(O)N(R⁰)₂, —N(R⁰)C(S)N(R⁰)₂, —NR⁰CO₂R⁰, —NR⁰NR⁰C(O)R⁰, —NR⁰ NR⁰C(O)N(R⁰)₂, —NR⁰ NR⁰CO₂R⁰, —C(O)C(O)R⁰,—C(O)CH₂C(O)R⁰, —(CH₂)₀₋₆—CO₂R⁰, —C(O)R⁰, —C(O)N(R⁰)N(R⁰)₂, —C(O)N(R⁰)₂,—C(O)N(R⁰)OH, —OC(O)R⁰, —C(O)N(R⁰)SO₂R⁰, —OC(O)N(R⁰)₂, —S(O)_(t)R⁰,—S(O)_(t)—OR⁰, —S(O)_(t)N(R⁰)C(O)R⁰, —S(O)_(t)N(R⁰)OR⁰, —NR⁰SO₂N(R⁰)₂,—NR⁰SO₂R⁰, —C(═S)N(R⁰)₂, —C(═N H)—N(R⁰)₂, —(CH₂)₁₋₆—C(O)R⁰,—C(═N—OR⁰)—N(R⁰)₂, —O—(CH₂)₀₋₆—SO₂N(R⁰)₂, —(CH₂)₁₋₆—NHC(O)R⁰, and—SO₂N(R⁰)₂ wherein the two R⁰s on the same nitrogen are optionally takentogether to form a 5-8 membered saturated, partially saturated, oraromatic ring having additional 0-4 heteroatoms selected from oxygen,phosphorus, nitrogen, or sulfur; each R⁸ is independently selected fromR⁷, ═O, ═S, ═N(R⁰), and ═N(CN); each R⁰ is independently selected fromthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,carbocyclylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,heterocyclyl, or heterocyclylalkyl, wherein each member of R⁰ except His optionally substituted by one or more R*, OR*, N(R*)₂, ═O, ═S, halo,CF₃, NO₂, CN, —C(O)R*, —CO₂R*, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-aralkyl, —S(O)_(t)-aryl, —S(O)_(t)-heteroaryl, —NR*SO₂R*,—NR*C(O)R*, —NR*C(O)N(R*)₂, —N(R*)C(S)N(R*)₂, —NR*CO₂R*, —NR*NR*C(O)R*,—NR*NR*C(O)N(R*)₂, —NR*NR*CO₂R*, —C(O)C(O)R*, —C(O)CH₂C(O)R*,—C(O)N(R*)N(R*)₂, —C(O)N(R*)₂, —C(O)NR*SO₂R*, —OC(O)N(R*)₂, —S(O)_(t)R*,—NR*SO₂N(R*)₂, and —SO₂N(R*)₂ wherein the two R*s on the same nitrogenare optionally taken together to form a 5-8 membered saturated,partially saturated or aromatic ring having additional 0-4 heteroatomsselected from oxygen, phosphorus, nitrogen or sulfur; and each R* isindependently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, orheteroaryl.
 2. The compound of claim 1 wherein R¹ is optionallysubstituted aryl.
 3. The compound of claim 2 wherein R¹ is phenyl mono-or di-substituted with halogen.
 4. The compound of claim 3 wherein R¹ isphenyl di-substituted with Cl.
 5. The compound of claim 1 wherein—(Y)_(m)—R³ is


6. The compound of claim 1 wherein —(Y)_(m)—R³ is


7. The compound of claim 1 wherein m is 1, Y is —C(O)—, and R³ is eitheraryl or heteroaryl wherein either is optionally substituted, optionallysubstituted alkyl, or optionally substituted cycloalkyl.
 8. The compoundof claim 1 wherein m is 1, Y is —(C═N—CN)—O—, and R³ is optionallysubstituted aryl, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heteroaryl, or optionally substitutedheterocyclyl.
 9. The compound of claim 1 wherein m is 1, Y is —(CH₂)—,and R³ is optionally substituted aryl.
 10. The compound of claim 1wherein m is 1, Y is —C(O)O—, and R³ is optionally substituted alkyl oroptionally substituted aryl.
 11. The compound of claim 1 wherein m is 0and R³ is optionally substituted heteroaryl or optionally substitutedheterocyclyl.
 12. The compound of claim 1 where X is —(CH₂)—,—(CH₂—CH₂)—, or —(CH₂—CH₂—CH₂)—.
 13. The compound of claim 12 wherein Xis optionally substituted by one or more halogen or oxo.
 14. Thecompound of claim 13 wherein X is disubstituted with halogen.
 15. Thecompound of claim 14 wherein X is disubstituted with fluoro.
 16. Thecompound of claim 15 wherein X is —(CF₂—CH₂)—.
 17. The compound of claim13 wherein X optionally has 1-3 heteroatoms selected from oxygen,phosphorus, sulfur, or nitrogen.
 18. The compound of claim 1 wherein theA ring is selected from the following, where the asterisk (*) indicatesthe preferred, but not limiting, point(s) of substitution:


19. The compound of claim 18 wherein each R², with an asteriskindicating a point of substitution from ring A, independently isselected from:


20. The compound of claim 1 wherein the A ring, with two geminal R²s, isselected from the group consisting of:


21. The compound of claim 1 wherein the A ring is tropane or piperidine,either optionally substituted with one or more R².
 22. The compound ofclaim 21 wherein the A ring in combination with R² is


23. The compound of claim 1 wherein the A ring contains at least oneadditional nitrogen atom and said A ring optionally is N-substituted.24. The compound of claim 23 wherein the A ring is N-substituted with—(CH₂)_(a)—(V_(b)—R+).
 25. The compound of claim 1 wherein ring B isselected from the group consisting of


26. A method of treatment of a viral infection in a mammal comprisingadministering to said mammal an antiviral effective amount of a compoundaccording to claim
 1. 27. A method according to claim 26 wherein theviral infection is an HIV infection.
 28. A method of treatment of abacterial infection in a mammal comprising administering to said mammalan effective amount of a compound according to claim 1
 29. A methodaccording to claim 28 wherein the bacterium is Yersinia pestis.
 30. Amethod of treatment of multiple sclerosis, rheumatoid arthritis,autoimmune diabetes, chronic implant rejection, asthma, rheumatoidarthritis, Crohns Disease, inflammatory bowel disease, chronicinflammatory disease, glomerular disease, nephrotoxic serum nephritis,kidney disease, Alzheimer's Disease, autoimmune encephalomyelitis,arterial thrombosis, allergic rhinitis, arteriosclerosis, Sjogren'ssyndrome, systemic lupus erythematosus, graft rejection, cancers withleukocyte infiltration of the skin or organs, infectious disordersincluding bubonic and pneumonic plague, human papilloma virus infection,prostate cancer, wound healing, amyotrophic lateral sclerosis and immunemediated disorders in a mammal comprising administering to said mammal apharmceutically effective amount of a compound according to claim
 1. 31.A compound according to claim 1 for use in medical therapy. 32-36.(canceled)
 37. A pharmaceutical composition comprising apharmaceutically effective amount of a compound according to claim 1together with a pharmaceutically acceptable carrier.
 38. Thepharmaceutical composition according to claim 37 in the form of a tabletor capsule.
 39. The pharmaceutical composition according to claim 37 inthe form of a liquid.
 40. A method of treatment or prevention of a viralinfection in a mammal comprising administering to said mammal acomposition comprising a compound according to claim 1 and anothertherapeutic agent.
 41. A method according to claim 40, wherein saidcomposition comprises another therapeutic agent selected from the groupconsisting of (1-alpha, 2-beta,3-alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine [(−)BHCG, SQ-34514,lobucavir], 9-[(2R,3R,4S)-3,4-bis(hydroxymethyl)-2-oxetanosyl]adenine(oxetanocin-G), acyclic nucleosides, acyclovir, valaciclovir,famciclovir, ganciclovir, penciclovir, acyclic nucleoside phosphonates,(S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC),[[[2-(6-amino-9H-purin-9-yl)ethoxy]methyl]phosphinylidene]bis(oxymethylene)-2,2-dimethylpropanoicacid (bis-POM PMEA, adefovir dipivoxil),[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid(tenofovir),(R)-[[2-(6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acidbis-(isopropoxycarbonyloxymethyl)ester (bis-POC-PMPA), ribonucleotidereductase inhibitors, 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl)thiocarbonohydrazone and hydroxyurea, nucleoside reverse transcriptaseinhibitors, 3′-azido-3′-deoxythymidine (AZT, zidovudine),2′,3′-dideoxycytidine (ddC, zalcitabine), 2′,3′-dideoxyadenosine,2′,3′-dideoxyinosine (ddI, didanosine), 2′,3′-didehydrothymidine (d4T,stavudine), (−)-beta-D-2,6-diaminopurine dioxolane (DAPD),3′-azido-2′,3′-dideoxythymidine-5′-H-phosphophonate (phosphonovir),2′-deoxy-5-iodo-uridine (idoxuridine),(−)-cis-1-(2-hydroxymethyl)-1,3-oxathiolane 5-yl)-cytosine (lamivudine),cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC),3′-deoxy-3′-fluorothymidine, 5-chloro-2′,3′-dideoxy-3′-fluorouridine,(−)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol(abacavir), 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G),ABT-606 (2HM-H2G) ribavirin, protease inhibitors, indinavir, ritonavir,nelfinavir, amprenavir, saquinavir, fosamprenavir,(R)-N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-N-[(R)-2-N-(isoquinolin-5-yloxyacetyl)amino-3-methylthiopropanoyl]amino-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide(KNI-272),4R-(4alpha,5alpha,6beta)]-1,3-bis[(3-aminophenyl)methyl]hexahydro-5,6-dihydroxy4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-onedimethanesulfonate (mozenavir),3-[1-[3-[2-(5-trifluoromethylpyridinyl)-sulfonylamino]phenyl]propyl]-4-hydroxy-6alpha-phenethyl-6beta-propyl-5,6-dihydro-2-pyranone(tipranavir),N′-[2(S)-Hydroxy-3(S)-[N-(methoxycarbonyl)-1-tert-leucylamino]-4-phenylbutyl-Nalpha-(methoxycarbonyl)-N′-[4-(2-pyridyl)benzyl]-L-tert-leucylhydrazide(BMS-232632),3-(2(S)-Hydroxy-3(S)-(3-hydroxy-2-methylbenzamido)-4-phenylbutanoyl)-5,5-dimethyl-N-(2-methylbenzyl)thiazolidine-4(R)-carboxamide(AG-1776), N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenyl-methyl-4(S)-hydroxy-5-(1-(1-(4-benzo[b]furanylmethyl)-2(S)-N′-(tert-butylcarboxamido)piperazinyl)pentanamide(MK-944A), interferons, α-interferon, renal excretion inhibitors,probenecid, nucleoside transport inhibitors, dipyridamole,pentoxifylline, N-acetylcysteine (NAC), Procysteine, α-trichosanthin,phosphonoformic acid, immunomodulators, interleukin II, thymosin,granulocyte macrophage colony stimulating factors, erythropoetin,soluble CD₄ and genetically engineered derivatives thereof,non-nucleoside reverse transcriptase inhibitors (NNRTIs), nevirapine(BI-RG-587),alpha-((2-acetyl-5-methylphenyl)amino)-2,6-dichloro-benzeneacetamide(loviride),1-[3-(isopropylamino)-2-pyridyl]-4-[5-(methanesulfonamido)-1H-indol-2-ylcarbonyl]piperazinemonomethanesulfonate (delavirdine), (10R, 11 S, 12S)-12-hydroxy-6, 6,10, 11-tetramethyl-4-propyl-11,12-dihydro-2H, 6H,10H-benzo(1,2-b:3,4-b′:5,6-b″)tripyran-2-one ((+) calanolide A),(4S)-6-Chloro-4-[1E)-cyclopropylethenyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (DPC-083),(S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one(efavirenz, DMP 266),1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-2,4(1H,3H)-pyrimidinedione(MKC-442), and5-(3,5-dichlorophenyl)thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethylcarbamate (capravirine), glycoprotein 120 antagonists, PRO-2000,PRO-542,1,4-bis[3-[(2,4-dichlorophenyl)carbonylamino]-2-oxo-5,8-disodiumsulfanyl]naphthalyl-2,5-dimethoxyphenyl-1,4-dihydrazone(FP-21399), cytokine antagonists, reticulose (Product-R),1,1′-azobis-formamide (ADA),1,11-(1,4-phenylenebis(methylene))bis-1,4,8,11-tetraazacyclotetradecaneoctahydrochloride (AMD-3100), integrase inhibitors, and fusioninhibitors.
 42. A method of treatment of a viral infection in a mammalcomprising administering to said mammal a composition comprising acompound according to claim 1 and ritonavir.